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WO1997046511A1 - Composes agissant sur un nouveau site des canaux a calcium actives par recepteur et utiles pour traiter des troubles et des maladies neurologiques - Google Patents

Composes agissant sur un nouveau site des canaux a calcium actives par recepteur et utiles pour traiter des troubles et des maladies neurologiques Download PDF

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Publication number
WO1997046511A1
WO1997046511A1 PCT/US1996/020697 US9620697W WO9746511A1 WO 1997046511 A1 WO1997046511 A1 WO 1997046511A1 US 9620697 W US9620697 W US 9620697W WO 9746511 A1 WO9746511 A1 WO 9746511A1
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WIPO (PCT)
Prior art keywords
compound
group
alkyl
methyl
pharmaceutically acceptable
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PCT/US1996/020697
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English (en)
Inventor
Alan L. Mueller
Scott T. Moe
Manuel F. Balandrin
Bradford C. Vanwagenen
Eric G. Delmar
Linda D. Artman
Robert M. Barmore
Daryl L. Smith
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Nps Pharmaceuticals, Inc.
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Application filed by Nps Pharmaceuticals, Inc. filed Critical Nps Pharmaceuticals, Inc.
Priority to AU13525/97A priority Critical patent/AU723349B2/en
Priority to CA002257234A priority patent/CA2257234C/fr
Priority to EP96945069A priority patent/EP0912494A1/fr
Priority to JP50053898A priority patent/JP2002511835A/ja
Publication of WO1997046511A1 publication Critical patent/WO1997046511A1/fr

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    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/12—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups
    • C07C233/13—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by halogen atoms or by nitro or nitroso groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
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    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/13—Amines
    • A61K31/135—Amines having aromatic rings, e.g. ketamine, nortriptyline
    • A61K31/137—Arylalkylamines, e.g. amphetamine, epinephrine, salbutamol, ephedrine or methadone
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
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    • C07C217/04—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated
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    • C07C217/08—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to an acyclic carbon atom
    • C07C217/10—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being acyclic and saturated having only one etherified hydroxy group and one amino group bound to the carbon skeleton, which is not further substituted the oxygen atom of the etherified hydroxy group being further bound to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical containing six-membered aromatic rings
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    • C07C217/58—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms with amino groups and the six-membered aromatic ring, or the condensed ring system containing that ring, bound to the same carbon atom of the carbon chain
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    • C07C217/56—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by singly-bound oxygen atoms
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Definitions

  • This invention relates to compounds useful as neuroprotectants , ant convulsants, anxiolytics, analgesics, muscle relaxants or adjuvants to general anesthetics.
  • the invention relates as well to methods useful for the treatment of neurological disorders and diseases, including, but not limited to, global and focal ischemic and hemorrhagic stroke, head trauma, spinal cord injury, hypoxia-induced nerve cell damage such as in cardiac arrest or neonatal distress, epilepsy, anxiety, and neurodegenerative diseases such as Alzheimer's Disease, Huntington's Disease, Parkinson's Disease, and amyotrophic lateral sclerosis (ALS) .
  • neurological disorders and diseases including, but not limited to, global and focal ischemic and hemorrhagic stroke, head trauma, spinal cord injury, hypoxia-induced nerve cell damage such as in cardiac arrest or neonatal distress, epilepsy, anxiety, and neurodegenerative diseases such as Alzheimer's Disease, Huntington's Disease, Parkinson's Disease, and amyotrophic lateral sclerosis
  • the invention relates as well to methods of screening for compounds active at a novel site on receptor-operated calcium channels, and thereby possessing therapeutic utility as neuroprotectants, anticonvulsants, anxiolytics, analgesics, muscle relaxants or adjuvants to general anesthetics, and/or possessing potential therapeutic utility for the treatment of neurological disorders and diseases as described above .
  • Glutamate is the major excitatory neurotransmitter in the mammalian brain. Glutamate binds or interacts with one or more glutamate receptors which can be differentiated pharmacologically into several subtypes. In the mammalian central nervous system (CNS) there are three main subtypes of ionotropic glutamate receptors, defined pharmacologically by the selective agonists N-methyl-D-aspartate (NMDA) , kainate (KA) , and ⁇ -amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) .
  • NMDA N-methyl-D-aspartate
  • KA kainate
  • AMPA ⁇ -amino-3-hydroxy-5-methylisoxazole-4-propionic acid
  • the NMDA receptor has been implicated in a variety of neurological pathologies including stroke, head trauma, spinal cord injury, epilepsy, anxiety, and neurodegenerative diseases such as Alzheimer's Disease (Watkins and Collingridge, The NMDA Receptor, Oxford: IRL Press, 1989) .
  • a role for NMDA receptors in nociception and analgesia has been postulated as well (Dickenson, A cure for wind-up: NMDA receptor antagonists as potential analgesics. Trends Pharmacol . Sci . 11: 307, 1990) .
  • AMPA receptors More recently, AMPA receptors have been widely studied for their possible contributions to such neurological pathologies (Fisher and Bogousslavsky, Evolving toward effective therapy for acute ischemic stroke. J " .
  • AMPA/kainate antagonists Comparison of GYKI 52466 and NBQX in maximal electroshock and chemoconvulsant seizure models. Epilepsy Res . 15: 179, 1993) .
  • the NMDA receptor When activated by glutamate, the endogenous neurotransmitter, the NMDA receptor permits the influx of extracellular calcium (Ca 2 *) and sodium (Na*) through an associated ion channel.
  • the NMDA receptor allows considerably more influx of Ca 2 * than do kainate or AMPA receptors (but see below) , and is an example of a receptor-operated Ca 2 " channel. Normally, the channel is opened only briefly, allowing a localized and transient increase in the concentration of intracellular Ca 2 * ([Ca *] , which, in turn, alters the functional activity of the cell. However, prolonged increases in [Ca 2 *] 1( resulting from chronic stimulation of the NMDA receptor, are toxic to the cell and lead to cell death.
  • N-methyl -D- aspartate antagonists for antianxiety effects A review. In: Mul tipl e Sigma and PCP Receptor Ligands : Mechanisms for Neuromodula tion and Neuroprotection ? ⁇ PP Books, Ann Arbor, Michigan, pp. 801-815, 1992) , neurodegenerative diseases (Meldrum and Garthwaite, Excitatory amino acid neurotoxicity and neurodegenerative disease. Trends Pharmacol . Sci . 11: 379, 1990) , and hyperalgesic states (Dickenson, A cure for wind-up: MDA receptor antagonists as potential analgesics. Trends Pharmacol . Sci . 11: 307, 1990) .
  • the activity of the ⁇ MDA receptor-ionophore complex is regulated by a variety of modulatory sites that can be targeted by selective antagonists .
  • Competitive antagonists such as the phosphonate AP5
  • noncornpetitive antagonists such as phencyclidine (PCP) , MK-801 or magnesium (Mg 2 *)
  • PCP phencyclidine
  • MK-801 or magnesium (Mg 2 *) act within the associated ion channel (ionophore)
  • glycine acts as a co-agonist, so that both glutamate and glycine are necessary to fully elicit ⁇ MDA receptor-mediated responses.
  • Other potential sites for modulation of ⁇ MDA receptor function include a zinc (Zn 2+ ) binding site and a sigma ligand binding site.
  • endogenous polyamines such as spermine are believed to bind to a specific site and so potentiate NMDA receptor function (Ransom and Stec, Cooperative modulation of [ 3 H]MK-801 binding to the NMDA receptor-ion channel complex by glutamate, glycine and polyamines. J. Neurochem. 51: 830, 1988) .
  • the potentiating effect of polyamines on NMDA receptor function may be mediated via a specific receptor site for polyamines; polyamines demonstrating agonist, antagonist, and inverse agonist activity have been described (Reynolds, Arcaine is a competitive antagonist of the polyamine site on the NMDA receptor. Europ. J. Pharmacol .
  • NMDARl and NMDAR2A through NMDAR2D encoded by a distinct gene
  • NMDARl alternative splicing gives rise to at least six additional isoforms. It appears that NMDARl is a necessary subunit, and that combination of NMDARl with different members of NMDAR2 forms the fully functional NMDA receptor-ionophore complex.
  • the NMDA receptor-ionophore complex thus, can be defined as a hetero-oligomeric structure composed of at least NMDARl and NMDAR2 subunits; the existence of additional, as yet undiscovered, subunits is not excluded by this definition.
  • NMDARl has been shown to possess binding sites for glutamate, glycine, Mg 2 *, MK-801, and Zn 2 *.
  • the binding sites for sigma ligands and polyamines have not yet been localized on NMDA receptor subunits, although ifenprodil recently has been reported to be more potent at the NMDAR2B subunit than at the NMDAR2A subunit (Williams, Ifenprodil discriminates subtypes of the N-methyl -D-aspartate receptor: selectivity and mechanisms at recombinant heteromeric receptors. Mol. Pharmacol. 44: 851, 1993) .
  • AMPA receptors designated GluRl, GluR2, GluR3 , and GluR4 (also termed GluRA through GluRD) , each of which exists in one of two forms, termed flip and flop, which arise by R ⁇ A alternative splicing.
  • GluRl, GluR3 and GluR4 when expressed as homomeric or heteromeric receptors, are permeable to Ca 2 *, and are therefore examples of receptor-operated Ca 2 * channels.
  • the GluR2 subunit is functionally distinct by virtue of the fact that it contains an arginine residue within the putative pore-forming transmembrane region II; GluRl, GluR3 and GluR4 all contain a glutamine residue in this critical region (termed the Q/R site, where Q and R are the single letter designations for glutamine and arginine, respectively) .
  • the activity of the AMPA receptor is regulated by a number of odulatory sites that can be targeted by selective antagonists (Honore et al . , Quinoxalinediones : potent competitive non-NMDA glutamate receptor antagonists.
  • NMDA receptor Compounds that act as competitive or noncompetitive antagonists at the NMDA receptor are said to be effective in preventing neuronal cell death in various in vi tro neurotoxicity assays (Meldrum and Garthwaite, Excitatory amino acid neurotoxicity and neurodegenerative disease. Trends Pharmacol . Sci . 11: 379, 1990) and in in vi vo models of stroke (Scatton, Therapeutic potential of NMDA receptor antagonists in ische ic cerebrovascular disease in Drug Strategies in the Prevention and Trea tment of Stroke, IBC Technical Services Ltd., 1990) .
  • Such compounds are also effective anticonvulsants (Meldrum, Excitatory amino acid neurotransmission in epilepsy and anticonvulsant therapy in Excitatory Amino Acids .
  • NMDA receptor antagonists may lessen dementia associated with Alzheimer's Disease (Hughes, Merz' novel approach to the treatment of dementia. Script No. 1666: 24, 1991) .
  • AMPA receptor antagonists have come under intense scrutiny as potential therapeutic agents for the treatment of such neurological disorders and diseases.
  • AMPA receptor antagonists have been shown to possess neuroprotectant (Fisher and Bogousslavsky, Evolving toward effective therapy for acute ischemic stroke. J. Amer. Med . Assoc . 270: 360, 1993) and anticonvulsant (Ya aguchi et al . , Anticonvulsant activity of AMPA/kainate antagonists: comparison of GYKI 52466 and NBQX in maximal electroshock and chemoconvulsant seizure models. Epil epsy Res . 15: 179, 1993) activity in animal models of ischemic stroke and epilepsy, respectively.
  • the nicotinic cholinergic receptor present in the mammalian CNS is another example of a receptor-operated Ca 2 * channel (Deneris et al . , Pharmacological and functional diversity of neuronal nicotinic acetylcholine receptors. Trends Pharmacol .
  • arylalkylamine toxins also called polyamine toxins, arylamine toxins, acylpolyamine toxins or polyamine amide toxins
  • arylalkylamine toxins also called polyamine toxins, arylamine toxins, acylpolyamine toxins or polyamine amide toxins
  • argiotoxin 636 exerts a novel inhibitory effect on the NMDA receptor complex by binding to one of the Mg 2 * sites located within the
  • NMDA-gated ion channel Binding data reported by Williams et al . also support the conclusion that argiotoxin 636 does not act primarily at the polyamine modulatory site on the NMDA receptor, but rather acts directly to produce an activity-dependent block of the ion channel. It is already known that compounds such as phencyclidine and ketamine can block the ion channels associated with both arthropod muscle glutamate receptors and mammalian NMDA receptors. Thus, it seems possible that vertebrate and invertebrate glutamate receptors share additional binding sites for allosteric modulators of receptor function, perhaps related to divalent cation-binding sites. Clearly, considerable additional work will be needed to determine if the arylammes define such a novel regulatory site.
  • Affecting Glutamate Receptors Polyamines in Therapeutic Neurochemistry. Pharmacol . Therap . 52: 245, 1991
  • arylalkylamine toxins polyamine amide toxins located within the membrane potential field referred to as the QUIS-R channel selectivity filter.
  • one such toxin, arg ⁇ otoxm-636 selectively antagonizes the NMDA receptor in cultured rat cortical neurons.
  • polyamines may antagonize responses to NMDA by interacting with membrane ion channels.
  • Herold and Yaksh esthesia and muscle relaxation with intrathecal injections of AR636 and AG489, two acylpolyamine spider toxins, in rats.
  • ⁇ -agatoxms can interact at the positive allosteric polyamine site on the NMDA receptor, stimulatory effects produced by this interaction may be masked in functional assays due to a separate action of the toxins as high-affinity, noncompetitive antagonists of the receptor.
  • Brackley et al (Selective antagonism of native and cloned kainate and NMDA receptors by polyamine-containing toxins, J. Pharmacol . Exp . Therap . 266: 1573, 1993) report that the polyamine-containing toxins (arylalkylamines) philanthotoxin-343 (PhTX-343) and argiotoxin-636 (Arg-636) produce reversible, noncompetitive, partly voltage-dependent antagonism of kainate- and NMDA-induced currents in Xenopus oocytes injected with rat brain RNA.
  • polyamine-containing toxins arylalkylamines
  • philanthotoxin-343 PhTX-343
  • argiotoxin-636 Argiotoxin-636
  • PhTX highly potent photoaffinity labeled philanthotoxin
  • arylalkylamines sometimes referred to as arylamine toxins, polyamine toxins, acylpolyamine toxins or polyamine amide toxins
  • arylalkylamines sometimes referred to as arylamine toxins, polyamine toxins, acylpolyamine toxins or polyamine amide toxins
  • these arylalkylamine compounds contain within their structure a polyamine moiety, they are unlike other known simple polyamines in possessing extremely potent and specific effects on certain types of receptor-operated Ca 2 * channels.
  • arylalkylamines Using native arylalkylamines as lead structures, a number of analogs were synthesized and tested. Initial findings on arylalkylamines isolated and purified from venom were confirmed utilizing synthetic arylalkylamines. These compounds are small molecules (mol. wt . ⁇ 800) with demonstrated efficacy in in vivo models of stroke and epilepsy.
  • the NMDA receptor-ionophore complex was used as a model of receptor-operated Ca 2 * channels. Selected arylalkylamines were shown to block NMDA receptor-mediated responses by a novel mechanism.
  • the unique behavioral pharmacological profile of these compounds suggests that they are unlikely to cause the PCP-like psychotomimetic activity and cognitive deficits that characterize other inhibitors of the NMDA receptor.
  • the arylalkylamines are unique amongst NMDA receptor antagonists in that they are able to antagonize certain subtypes of cloned and expressed AMPA receptors, namely, those permeable to Ca 2* .
  • the arylalkylamines therefore, are the only known class of compounds able to antagonize glutamate receptor-mediated increases in cytosolic Ca 2 * regardless of the pharmacological definition of receptor subtype.
  • arylalkylamines inhibit another receptor-operated Ca 2* channel, the nicotinic cholinergic receptor. Given that excessive and prolonged increases in cytosolic Ca 2* have been implicated in the etiology of several neurological disorders and diseases, such arylalkylamines are valuable small molecule leads for the development of novel therapeutics for various neurological disorders and diseases.
  • Applicant has determined that the selected arylalkylamines bind with high affinity at a novel site on the NMDA receptor-ionophore complex which has heretofore been unidentified, and that said arylalkylamines do not bind with high affinity at any of the known sites (glutamate binding site, glycine binding site, MK-801 binding site, Mg 2 * binding site, Zn 2 * binding site, polyamine binding site, sigma binding site) on said NMDA receptor-ionophore complex.
  • This determination has allowed applicant to develop methods and protocols by which useful compounds can be identified which provide both therapeutically useful compounds and lead compounds for the development of other therapeutically useful compounds. These compounds can be identified by screening for compounds that bind at this novel arylalkylamine binding site, and by determining whether such a compound has the required biological, pharmacological and physiological properties .
  • the method includes the step of identifying a compound which binds to the receptor-operated Ca 2* channel at that site bound by the arylalkylamine compounds referred to herein as Compound 1, Compound 2 or Compound 3, and having the structures shown below.
  • terapéuticaally useful compound is meant a compound that is potentially useful in the treatment of a disorder or disease state.
  • a compound uncovered by the screening method is characterized as having potential therapeutic utility in treatment because clinical tests have not yet been conducted to determine actual therapeutic utility.
  • neurodegenerative disease is meant a disorder or disease of the nervous system including, but not limited to, global and focal ischemic and hemorrhagic stroke, head trauma, spinal cord injury, spinal cord ischemia, ischemia- or hypoxia-induced nerve cell damage, hypoxia-induced nerve cell damage as in cardiac arrest or neonatal distress, epilepsy, anxiety, neuropsychiatric or cognitive deficits due to ischemia or hypoxia such as those that frequently occur as a consequence of cardiac surgery under cardiopulmonary bypass, and neurodegenerative disease.
  • neurodegenerative disease is meant diseases including, but not limited to, Alzheimer's Disease, Huntington's Disease, Parkinson's Disease, and amyotrophic lateral sclerosis (ALS) .
  • neuroprotectant is meant a compound capable of preventing the neuronal damage or death associated with a neurological disorder or disease.
  • anticonvulsant is meant a compound capable of reducing convulsions produced by conditions such as simple partial seizures, complex partial seizures, status epilepticus, and trauma-induced seizures such as occur following head injury, including head surgery.
  • anxiolytic is meant a compound capable of relieving the feelings of apprehension, uncertainty and fear that are characteristic of anxiety.
  • analgesic is meant a compound capable of relieving pain by altering perception of nociceptive stimuli without producing anesthesia or loss of consciousness .
  • muscle relaxant is meant a compound that reduces muscular tension.
  • abjunct in general anesthesia is meant a compound useful conjunction with anesthetic agents in producing the loss of ability to perceive pain associated with the loss of consciousness.
  • potent or “active” is meant that the compound has activity at receptor-operated calcium channels, including NMDA receptors, Ca 2* -permeable AMPA receptors, and nicotinic cholinergic receptors, with an IC 50 value less than 10 ⁇ M, more preferably less than 100 nM, and even more preferably less than 1 nM.
  • selective is meant that the compound is potent at receptor-operated calcium channels as defined above, but is less potent by greater than 10-fold, more preferably 50-fold, and even more preferably 100-fold, at other neurotransmitter receptors, neurotransmitter receptor-operated ion channels, or voltage-dependent ion channels.
  • biochemical and electrophysiological assays of receptor-operated calcium channel function is meant assays designed to detect by biochemical or electrophysiological means the functional activity of receptor-operated calcium channels.
  • assays include, but are not limited to, the fura-2 fluorimetric assay for cytosolic calcium cultured rat cerebellar granule cells (see Example 1 and Example 2) , patch clamp electrophysiolocial assays (see Example 3 and Example 27) , rat hippocampal slice synaptic transmission assays (see Example 5) , radioligand binding assays (see Example 4, Example 24, Example 25, and Example 26), and m vi tro neuroprotectant assays (see Example 6) .
  • ischemic and hemorrhagic stroke head trauma, spinal cord injury, spinal cord ischemia, ischemia- or hypoxia- induced nerve cell damage, hypoxia-induced nerve cell damage as in cardiac arrest or neonatal distress, neuropsychiatric or cognitive deficits due to ischemia or hypoxia such as those that frequently occur as a consequence of cardiac surgery under cardiopulmonary bypass, and neurodegenerative diseases such as Alzheimer's Disease, Huntington's Disease, Parkinson's Disease, and amyotrophic lateral sclerosis (ALS) (see Examples 7 and 8, below) .
  • ALS amyotrophic lateral sclerosis
  • anticonvulsant activity is meant efficacy in reducing convulsions produced by conditions such as simple partial seizures, complex partial seizures, status epilepticus, and trauma-induced seizures such as occur following head injury, including head surgery (see Examples 9 and 10, below) .
  • anxiolytic activity is meant that a compound reduces the feelings of apprehension, uncertainty and fear that are characteristic of anxiety.
  • analgesic activity is meant that a compound produces the absence of pain in response to a stimulus that would normally be painful. Such activity would be useful in clinical conditions of acute and chronic pain including, but not limited to the following: preemptive preoperative analgesia; peripheral neuropathies such as occur with diabetes mellitus and multiple sclerosis; phantom limb pain; causalgia; neuralgias such as occur with herpes zoster; central pain such as that seen with spinal cord lesions; hyperalgesia; and allodynia.
  • central pain is meant pain associated with a lesion of the central nervous system.
  • hypoalgesia is meant an increased response to a stimulus that is normally painful.
  • allodynia is meant pain due to a stimulus that does not normally provoke pain (see Examples 11 through 14, below) .
  • ERTAIN dose is meant an amount of a compound that relieves to some extent one or more symptoms of the disease or condition of the patient. Additionally, by “therapeutic dose” is meant an amount that returns to normal, either partially or completely, physiological or biochemical parameters associated with or causative of the disease or condition. Generally, it is an amount between about 1 nmole and 1 ⁇ ole of the compound, dependent on its EC SQ (IC S0 in the case of an antagonist) and on the age, size, and disease associated with the patient.
  • impair cognition is meant the ability to impair the acquisition of memory or the performance of a learned task (see Example 20) .
  • impair congnition is meant the ability to interfere with normal rational thought processes and reasoning.
  • disrupt motor function is meant the ability to significantly alter locomotor activity (see
  • Example 15 or elicit significant ataxia, loss of the righting reflex, sedation or muscle relaxation (see
  • Example 16 By “locomotor activity” is meant the ability to perform normal ambulatory movements.
  • loss of the righting reflex is meant the ability of an animal, typically a rodent, to right itself after being placed in a supine position.
  • neurovascular vacuolization is meant the production of vacuoles in neurons of the cingulate cortex or retrosplenial cortex (see Example 18) .
  • cardiovascular activity is meant the ability to elicit significant changes in parameters including, but not limited to, mean arterial blood pressure and heart rate (see Examples 21 and 22) .
  • hypoexcitability is meant an enhanced susceptibility to an excitatory stimulus.
  • Hyperexcitability is often manifested as a significant increase in locomotor activity in rodents administered a drug (see Example 15) .
  • sedation is meant a calmative effect, or the allaying of activity and excitement. Sedation is often manifested as a significant decrease in locomotor activity in rodents administered a drug (see Example
  • PCP-like abuse potential is meant the potential of a drug to be wrongfully used, as in the recreational use of PCP (i.e., "angel dust") by man. It is believed that PCP-like abuse potential can be predicted by the ability of a drug to generalize to PCP in rodents trained to discriminate PCP from saline (see Example 17. )
  • PCP generalization to PCP
  • a compound is perceived as being PCP in rodents trained to discriminate PCP from saline (see Example 17) .
  • PCP-like psychotomimetic activity is meant the ability of a drug to elicit in man a behavioral syndrome resembling acute psychosis, including visual hallucinations, paranoia, agitation, and confusion. It is believed that PCP-like psychotomimetic activity can be predicted in rodents by the ability of a drug to produce PCP-like stereotypic behaviors including ataxia, head weaving, hyperexcitability, and generalization to PCP in rodents trained to discriminate PCP from saline (see Example 15, Example 16, and Example 17) .
  • anterior is meant a deficit muscular coordination.
  • head weaving is meant the stereotypic behavior elicited in rodents by PCP in which the head is repeatedly moved slowly and broadly from side to side.
  • composition a therapeutically effective amount of a compound of the present invention in a pharmaceutically acceptable carrier, i.e., a formulation to which the compound can be added to dissolve or otherwise facilitate administration of the compound.
  • pharmaceutically acceptable carriers include water, saline, and physiologically buffered saline.
  • Such a pharmaceutical composition is provided in a suitable dose.
  • Such compositions are generally those which are approved for use in treatment of a specified disorder by the FDA or its equivalent in non-U.S. countries.
  • the invention features a method for treating a neurological disease or disorder, comprising the step of administering a pharmaceutical composition comprising a compound which binds to a receptor-operated calcium channel at the site bound by one of the arylalkylamines Compound 1, Compound 2 and Compound 3 , said compound being a potent and selective noncompetitive antagonist at such a receptor-operated calcium channel, and having one or more of the following pharmacological and physiological properties: efficacy in m vi tro biochemical and electrophysiological assays of receptor-operated calcium channel function, m vivo anticonvulsant activity, m vivo neuroprotectant activity, in vivo anxiolytic activity, and in vi vo analgesic activity; said compound also possessing one or more of the following pharmacological effects: the compound does not interfere with the induction of long-term potentiation rat hippocampal slices, and, at a therapeutic dose, does not impair cognition, does not disrupt motor performance, does not produce
  • minimal is meant that any side effect of the drug is tolerated by an average individual, and thus that the drug can be used for therapy of the target disease Such side effects are well known in the art and are routinely regarded by the FDA as minimal when it approves a drug for a target disease .
  • Treatment involves the steps of first identifying a patient that suffers from a neurological disease or disorder by standard clinical methodology and then treating such a patient with a composition of the present invention.
  • the invention features compounds useful for treating a patient having a neurological disease or disorder wherein said compound is a polyamine-type compound or an analog thereof (i.e., a polyheteroatomic molecule) having the formula
  • Ar is an appropriately substituted aromatic ring, ring system or other hydrophobic entity
  • Ar can be an aromatic (e.g. , carbocyclic aryl groups such as phenyl and bicyclic carbocyclic aryl ring systems such as naphthyl, 1, 2 , 3 , 4-tetrahydronaphthyl, indanyl, and indenyl) , heteroaromatic (e.g., indolyl, dihydroindolyl, quinolinyl and isoquinolinyl, and their respective 1, 2 , 3 , 4-tetrahydro- and 2-oxo- derivatives) , alicyclic (cycloaliphatic) , or heteroalicyclic ring or ring system (mono-, bi-, or tricyclic) , having 5- to 7-membered ring(s) optionally substituted with 1 to 5 substituents independently selected from lower alkyl of 1 to 5 carbon atoms, lower haloalky
  • the compound is selected from the group of Compounds 4 through 18, where such compounds have the formulae :
  • [ 3 H]MK-801 at concentrations ranging approximately 1 to 400-fold higher than those which antagonize NMDA receptor-mediated function.
  • Such simplified arylalkylamines possess one or more of the following additional biological properties: significant neuroprotectant activity, significant anticonvulsant activity, significant analgesic activity, no PCP-like stereotypic behavior in rodents (hyperexcitability and head weaving) at effective neuroprotectant, anticonvulsant and analgesic doses, no generalization to PCP in a PCP discrimination assay at effective neuroprotectant, anticonvulsant and analgesic doses, no neuronal vacuolization at effective neuroprotectant, anticonvulsant and analgesic doses, significantly less potent activity against voltage-sensitive calcium channels, and minimal hypotensive activity at effective neuroprotectant, anticonvulsant and analgesic doses.
  • Such compounds may, however, inhibit the induction of LTP in rat hippocampal slices and may produce motor impairment at neuroprotectant
  • One aspect of the invention features a method for treating a patient having a neurological disease or disorder, comprising administering a compound of Formula I:
  • R 1 and R 5 are independently selected from the group consisting of phenyl, benzyl, and phenoxy (each of which is optionally substituted with alkyl, hydroxyalkyl, -OH, -O-alkyl, -0-acyl, -F, -Cl, -Br, -I, -CF 3 or -0CF 3 ) , -H, alkyl, hydroxyalkyl, -OH, -O-alkyl, and O-acyl;
  • R 2 and R 6 are independently selected from the group consisting of -H, alkyl, and hydroxyalkyl; or R 2 and R 6 together are imino; or R 1 and R 2 together are -(CH 2 ) n - or - (CH 2 ) n -N(R 3 ) -(CH 2 ) n -;
  • R 3 is independently selected from the group consisting of -H, alkyl, 2-hydroxyethyl and alkylphenyl; n is an integer from 0 to 6, but at least one n must be greater than 0 ;
  • R 4 is selected from the group consisting of thiofuran, py ⁇ dyl, phenyl, benzyl, phenoxy, and phenylthio (each of which is optionally substituted with alkyl, -F, -Cl, -Br, -I, -CF 3 , -OH, -0CF 3 , -O-alkyl, or -O-acyl) , -H, alkyl and cycloalkyl;
  • X is independently selected from the group consisting of phenyl, benzyl, and phenoxy (each of which is optionally substituted with -F, -Cl, -Br, -I, -CF 3 , alkyl, -OH, -0CF 3 , -O-alkyl, or -O-acyl) -F, -Cl, -Br, -I, CF 3 , alkyl, -OH, -OCF 3 , -O-alkyl, and O-acyl; m is independently an integer from 0 to 5; Y is -NR 3 R 3 , except when R l and R 2 together are - (CH 2 ) n -N(R 3 ) - (CH 2 ) deliberately-, then Y is -H; and pharmaceutically acceptable salts and complexes thereof, wherein the compound is active at an NMDA receptor.
  • patient is meant any animal that has a cell with an NMDA receptor.
  • the animal is a mammal.
  • the animal is a human.
  • alkyl is meant a branched or unbranched hydrocarbon chain containing between 1 and 6, preferably between 1 and 4, carbon atoms, such as, e.g., methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, 2-methylpentyl, cyclopropyl ethyl, allyl, and cyclobutylmethyl .
  • lower alkyl is meant a branched or unbranched hydrocarbon chain containing between 1 and 4 carbon atoms, of which examples are listed herein.
  • hydroxyalkyl is meant an alkyl group as defined above, substituted with a hydroxyl group.
  • alkylphenyl is meant an alkyl group as defined above, substituted with a phenyl group.
  • acyl is meant -C(0)R, where R is H or alkyl as defined above, such as, e.g., formyl , acetyl , propionyl, or butyryl; or,
  • R is -O-alkyl such as in alkyl carbonates or R is N-alkyl such as in alkyl carbamates .
  • cycloalkyl is meant a branched or unbranched cyclic hydrocarbon chain containing between 3 and 12 carbon atoms .
  • Y is selected from the group consisting of -NH 2 and -NH-methyl;
  • R 4 is thiofuran, pyridyl , phenyl, benzyl, phenoxy, or phenylthio, each of which is optionally substituted with -F, -Cl, -Br, -I, -CF 3 , alkyl, -OH, -OCF 3 , -O-alkyl, or -O-acyl;
  • X is independently selected from the group consisting of meta-fluoro, meta-chloro, ortho-O-lower alkyl, ortho-methyl, ortho-fluoro, ortho-chloro, meta-O- lower alkyl, meta-methyl, ortho-OH, and meta-OH; and either
  • R ⁇ R 2 ' R 5 , and R 6 are -H; or R 2 is methyl, and R 1 , R 5 , and R 6 are -H; or R 1 is methyl, and R 2 , R 5 , and R 6 are -H.
  • R 1 and R 5 are independently selected from the group consisting of -H, lower alkyl, hydroxyalkyl, -OH, -O-alkyl, and -O-acyl;
  • R 2 and R 6 are independently selected from the group consisting of -H, lower alkyl, and hydroxyalkyl; or R 1 and R 2 together are -(CH 2 ) n - or
  • R 3 is independently selected from the group consisting of -H and lower alkyl
  • R 4 is selected from the group consisting of thiofuran, pyridyl, phenyl, benzyl, phenoxy, and phenylthio (each of which is optionally substituted with lower alkyl, -F, -Cl, -Br, -I, -CF 3 , -OH, -OCF 3 ,
  • X is independently selected from the group consisting of -F, -Cl, -Br, -I, -CF 3 , lower alkyl, -OH, and -OCF 3 ;
  • m is independently an integer from 0 to 5;
  • Y is -NHR 3 , or hydrogen when R 1 and R 2 together are
  • the invention features a method for treating a patient having a neurological disease or disorder comprising administering a compound of Formula II:
  • X is independently selected from the group consisting of -H, -Br, -Cl, -F, -I, -CF,, alkyl, -OH, -OCF 3 , -O-alkyl, and -O-acyl;
  • R 1 is independently selected from the group consisting of -H, alkyl, hydroxyalkyl, -OH, -O-alkyl, and -O-acyl
  • R 2 is independently selected from the group consisting of -H, alkyl, and hydroxyalkyl, or both R 2 s together are imino
  • R 3 is independently selected from the group consisting of -H, alkyl, 2-hydroxyethyl, and alkylphenyl
  • m is independently an integer from 0 to 5.
  • the compounds include the compound of Formula I, wherein:
  • X is independently selected from the group consisting of -F, -Cl, -Br, -I, -CF 3 , alkyl, -OH, -OCF 3 , -O-alkyl, and -O-acyl;
  • R 1 is selected from the group consisting of -H, alkyl, hydroxyalkyl, -OH, -O-alkyl, and -O-acyl;
  • R 2 and R 6 are independently selected from the group consisting of -H, alkyl, and hydroxyalkyl, or R 2 and R ⁇ together are imino;
  • R 5 is selected from the group consisting of -H, alkyl, hydroxyalkyl, -OH, -O-alkyl, and -O-acyl;
  • Y is NR 3 R 3 ;
  • R 4 is phenyl, optionally substituted with alkyl, -F, -Cl, -Br, -I, -CF 3 , -OH, -0CF 3 , -O-alkyl, or -O-acyl.
  • the administered compound has the structure of Formula III:
  • X is independently selected from the group consisting of -H, -Br, -Cl, -F, -I, -CF 3 , alkyl, -OH, -OCF 3 , -O-alkyl, and -O-acyl.
  • R 1 is independently selected from the group consisting of -H, alkyl, hydroxyalkyl, -OH, -O-alkyl, and -O-acyl;
  • R 2 is independently selected from the group consisting of -H, alkyl, and hydroxyalkyl, or both R 2 s together are imino;
  • R 3 is independently selected from the group consisting of -H, alkyl, 2-hydroxyethyl, and alkylphenyl;
  • R 4 is selected from the group consisting of thiofuran, pyridyl, phenyl, benzyl, phenoxy, and phenylthio, (each of which is optionally substituted with (X)m) , alkyl, and cycloalkyl; and, m is independently an integer from 0 to 5.
  • the compounds include the compound of Formula I, wherein:
  • X is independently selected from the group consisting of -F, -Cl, -Br, -I, -CF 3 , alkyl, -OH, -OCF 3 , -O-alkyl, and -O-acyl;
  • R 1 is selected from the group consisting of -H, alkyl, hydroxyalkyl, -OH, -O-alkyl, and -O-acyl;
  • R 2 and R 6 are selected from the group consisting of -H, alkyl, and hydroxyalkyl, or R 2 and R 6 together are imino;
  • R 5 is independently selected from the group consisting of -H, alkyl, hydroxyalkyl, -OH, -O-alkyl, and -O-acyl;
  • Y is NR 3 R 3 .
  • the administered compound has the structure of Formulas IV and V.
  • n is an integer from 1 to 6 ;
  • X is independently selected from the group consisting of -H, -Br, -Cl, -F, -I -CF 3 , alkyl, -OH, -0CF 3 , -O-alkyl, and -O-acyl;
  • R 3 is independently selected from the group consisting of -H, alkyl, 2-hydroxyethyl, and alkylphenyl; and m is independently an integer from 0 to 5.
  • the administered compounds include the compound of Formula I, wherein:
  • R 3 is independently selected from the group
  • R 4 is phenyl, optionally substituted with alkyl, -F, -Cl, -Br, -I, -CF 3 , -OH, -OCF 3 , -O-alkyl, or -O-acyl: and
  • R 1 and R 2 together are -(CH 2 ) n - or - (CH 2 ) n -N(R 3 ) - .
  • n is an integer from 1 to 6;
  • X is independently selected from the group 0 consisting of -H, -Br, -Cl, -F, -I, -CF 3 , alkyl, -OH, -0CF 3 , -O-alkyl, and -O-acyl;
  • R 3 is independently selected from the group consisting of -H, alkyl, 2-hydroxyethyl, and alkylphenyl;
  • R 4 is selected from the group consisting of thiofuran, pyridyl, phenyl, benzyl, phenoxy, and phenylthio (each of which is optionally substituted with (X)m) , alkyl, and cycloalkyl; and m is independently an integer from 0 to 5.
  • the administered compounds include the compound of Formula I, wherein:
  • X is independently selected from the group consisting of -F, -Cl, -Br, -I, CF 3 , alkyl, -OH, -0CF 3 , -O-alkyl, and -O-acyl-;
  • R 1 and R 2 together are -(CH 2 ) n - or - (CH 2 ) felicit-N(R 3 ) - . More preferred aspects are those embodiments in which:
  • X is independently selected from the group consisting of meta-fluoro, eta-chloro, ortho-O-lower alkyl, ortho-methyl, ortho-fluoro, ortho-chloro, meta-O-lower alkyl, meta-methyl, ortho-OH, and meta-OH;
  • NR 3 is selected from the group consisting of NH, N-methyl, and N-ethyl;
  • NR 3 R 3 is selected from the group consisting of NH 2/ NH-methyl, and NH-ethyl;
  • R 1 is selected from the group consisting of -H and methyl;
  • R 2 is selected from the group consisting of -H and methyl
  • R 4 is selected from the group consisting of phenyl, benzyl, and phenoxy, each of which is optionally substituted with alkyl, -F, -Cl, -Br, -F, -CF 3 , -OH, -OCF 3 , -O-alkyl, or -O-acyl.
  • X is meta-fluoro; each R 1 and R 2 is -H;
  • NR 3 is selected from the group consisting of NH and N-methyl
  • NR 3 R 3 is selected from the group consisting of NH 2 and NH-methyl
  • R 4 is selected from the group consisting of phenyl, benzyl, and phenoxy, each of which is optionally substituted with alkyl, -F, -Cl, -Br, -I, -CF 3 , -OH, -0CF 3 , -O-alkyl, or -O-acyl.
  • the invention features a method for treating a patient having a neurological disease or disorder comprising administering the compounds of Formula VIII:
  • X 1 and X 2 are independently selected from the group consisting of -F, -Cl, -CH 3 , -OH, and lower O-alkyl in the 1-, 3-, 7-, or 9-substituent positions; m is independently an integer from 0 to 2; -NHR is selected from the group consisting of -NH 2 , -NHCH 3 , and -NHC 2 H 5 ; R 1 is selected from the group consisting of -H, alkyl, hydroxyalkyl, -OH, -O-alkyl, and -O-acyl, and R 2 is selected from the group consisting of -H, alkyl, hydroxyalkyl, and pharmaceutically acceptable salts and complexes thereof, wherein the compound is active at an NMDA receptor.
  • X 1 or X 2 is -F, or both X 1 and X 2 are -F; either R 1 or R 2 is methyl or both R x and R 2 are -H; and
  • -NHR is selected from the group consisting of -NH 2 or -NHCH 3 .
  • the invention features a method for treating a patient having a neurological disease or disorder comprising administering the compounds of Formula IX: wherein:
  • W is selected from the group consisting of -CH 2 -, -0-, and -S-;
  • X 1 and X 2 are independently selected from the group consisting of -F, -Cl, -CH 3 , -OH, and lower O-alkyl;
  • m is independently an integer from 0 to 2;
  • -NHR is selected from the group consisting of -NH 2 , -NHCH 3 , and -NHC 2 H 5 ;
  • R 1 is selected from the group consisting of -H, alkyl, hydroxyalkyl, -OH, -O-alkyl, and -O-acyl; and
  • R 2 is selected from the group consisting of -H, alkyl, hydroxyalkyl, and pharmaceutically acceptable salts and complexes thereof, wherein the compound is active at an NMDA receptor.
  • the administered compound is selected from the group consisting of Compound 128, 129, 130, 131, 132, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, and 215.
  • the methods of treatment include administration of a compound selected from Compounds 19 through 215, or pharmaceutically acceptable salts and complexes thereof.
  • the compound has an IC 50 ⁇ 10 ⁇ M at an NMDA receptor, more preferably ⁇ 2.5 ⁇ M, and most preferably ⁇ 0.5 ⁇ M at an NMDA receptor.
  • the methods of treatment include administration of a compound selected from the group consisting of Compound 19, 20, 21, 22, 23, 24, 25, 27, 28, 29, 30, 31, 32, 33, 34, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 75, 76, 77, 78, 79, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 100, 101, 102, 103, 105, 106, 107, 108, 109, 111, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124,
  • the methods of treatment include administration of a compound selected from the group consisting of Compound 19, 20, 21, 22, 23, 24, 25, 27, 28, 29, 30, 31, 32, 33, 34, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 69, 70, 75, 76, 81, 82, 83, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 100, 101, 102, 103, 105, 106, 108, 109, 111, 115, 118, 119, 120, 121, 122, 125, 126, 127, 128, 129, 130, 131, 132, 133, 135, 136, 137, 138 (potential prodrug) , 139,
  • the compound is selected from the group consisting of Compound 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 69, 76, 82, 83, 88, 89, 90, 92, 93, 94, 95, 96, 101, 102, 103, 105, 109, 111, 115, 118, 119, 120, 121, 122, 125, 126, 127, 129, 130, 131, 135, 136, 137, 138, 139, 142, 144, 145, 148,
  • the methods of treatment include administration of a compound selected from the group consisting of Compound 19, 20, 21, 22, 23, 24, 25, 27, 28, 30, 31, 32, 33, 38, 39, 43, 44, 46, 47, 49, 50, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 69, 82, 83, 89, 90, 91, 93, 94, 95, 96, 97, 103, 111, 118, 119, 120, 122, 126, 135, 136, 137, 138 (potential prodrug) , 142, 144, 145, 147, 148, 149, and 150, and pharmaceutically acceptable salts and complexes thereof.
  • These compounds have an IC S0 ⁇ 0.5 ⁇ M at an NMDA receptor.
  • the methods of treatment include administration of a compound selected from the group consisting of Compound 20, 24, 25, 33, 50, 60, 66, 69, 103, 111, 118, 119, 120, 122, 136, 137, 138 (potential prodrug) , 142, 144, 145, 148, 149, and
  • the methods of treatment include administration of a compound selected from the group consisting of Compound 20, 33, 50, 60, 119, and 144, and pharmaceutically acceptable salts and complexes thereof.
  • the methods of treatment include administration of a compound selected from the group consisting of Compound 33, 50, 60, 119, and 144, and pharmaceutically acceptable salts and complexes thereof.
  • the invention provides a method for treating a patient having a neurological disease or disorder, comprising administering a compound which is selected from the group consisting of Compound 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 181, 182, 183, 184, 185, 186, 187, and pharmaceutically acceptable salts and complexes thereof.
  • These compounds have an IC 50 ⁇ lO ⁇ M at an NMDA receptor.
  • the invention provides a method for treating a patient having a neurological disease or disorder, comprising administering a compound which is selected from the group consisting of Compound 157, 158, 159, 163, 164, 166, 167, 168, 169, 170, 171, 181, 185, 186, and pharmaceutically acceptable salts and complexes thereof. These compounds have an IC 50 ⁇ lO ⁇ M at an NMDA receptor.
  • the invention provides a method for treating a patient having a neurological disease or disorder, comprising administering a compound which is selected from the group consisting of Compound 156, 157, 158, 159, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 181,
  • the invention provides a method for treating a patient having a neurological disease or disorder, comprising administering a compound which is selected from the group consisting of Compound 157, 158, 159, 163, 164,
  • the invention provides a method for treating a patient having a neurological disease or disorder, comprising administering a compound which is selected from the group consisting of Compound 156, 157, 158, 159, 161, 163, 164, 165, 167, 168, 169, 170, 171, 181, 186 and pharmaceutically acceptable salts and complexes thereof. These compounds have an IC S0 0.5 ⁇ M at an NMDA receptor.
  • the invention provides a method for treating a patient having a neurological disease or disorder, comprising administering a compound which is selected from the group consisting of Compound 157, 158, 159, 163, 164,
  • the invention provides a method for treating a patient having a neurological disease or disorder comprising administering a compound selected from the group consisting of Compounds 151 - 215, and pharmaceutically acceptable salts and complexes thereof.
  • the invention provides a method for treating a patient having a neurological disease or disorder comprising administering a compound selected from the group consisting of Compound 151, 152, 153, 154, 155, 157, 158, 159, 163, 164, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 181, 185, 186, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215 and pharmaceutically acceptable salts and complexes thereof .
  • the present invention provides simplified arylalkylamines comprising the compounds of Formulas I-IX and all preferred aspects of Formulas I-IX as set out above .
  • Examples of such simplified arylalkylamines include, but are not limited to, Compounds 19 - 215, whose structures are provided below.
  • the compound has an IC 50 ⁇ 10 ⁇ M at an NMDA receptor. More preferably, the compound has an IC 50 ⁇ 5 ⁇ M, more preferably ⁇ 2.5 ⁇ M, and most preferably ⁇ 0.5 ⁇ M at an NMDA receptor.
  • the compound is selected from the group consisting of Compound 21, 22, 23, 24, 25, 26, 27, 28, 29, 33, 34, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 69, 76, 78, 79, 82, 83, 84, 88, 89, 90, 92, 93, 94, 95, 96, 98, 101, 102, 103, 105, 107, 108, 109, 111, 115, 116, 118, 119, 120, 121, 122, 124, 125, 126, 127, 129, 130, 131, 134, 135, 136, 137, 138 (potential prodrug) , 139, 141, 142, 143, 144, 145, 148, 149, and 150.
  • the compound is selected from the group consisting of Compound 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66 , 69, 76, 82, 83, 88, 89, 90, 92, 93, 94, 95, 96, 101, 102, 103, 105, 109, 111, 115, 118, 119, 120, 121, 122, 125, 126, 127, 129, 130, 131, 135, 136, 137, 138, 139, 142, 144, 145, 148, 149, and 150.
  • the compound is selected from the group consisting of Compound 21, 22, 23, 24, 25, 27, 28, 29, 33, 34, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 69, 76, 82, 83, 88, 89, 90, 92, 93, 94, 95, 96, 101, 102, 103, 105, 108, 109, 111, 115, 118, 119, 120, 121, 122, 125, 126, 127, 129, 130, 131, 135, 136, 137, 138 (potential prodrug) , 139, 142, 144, 145, 148, 149, and 150.
  • These compounds have an IC 50 ⁇ 2.5 ⁇ M at an NMDA receptor.
  • the compound is selected from the group consisting of Compound 21, 22, 23, 24, 25, 27, 28, 33, 38, 39, 43, 44, 46, 47, 49, 50, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 69, 82, 83, 89, 90, 93, 94, 95, 96, 103, 111, 118, 119, 120, 122, 126, 135, 136, 137, 138 (potential prodrug) , 142, 144, 145, 148, 149, and 150.
  • These compounds have an IC S0 ⁇ ; 0.5 ⁇ M at an NMDA receptor.
  • the compound is selected from the group consisting of Compound 24, 25, 33, 50, 60, 66, 69, 103, 111, 118, 119, 120, 122, 136, 137, 138, 142, 144, 145, 148, 149, and 150.
  • the compound is selected from the group consisting of Compound 20, 33, 50, 60, 119, and 144.
  • the compound is selected from the group consisting of Compound 33, 50, 60, 119, and 144.
  • the compound is selected from the group consisting of Compound 151, 152, 153, 154, 155, 157, 158, 159, 163, 164, 166, 167, 168, 169, 170, 171, 172, 173, 174, 175, 176, 181, 185, 186, 188, 189, 190, 191, 192, 193, 194, 195, 196, 197, 198, 199, 200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210, 211, 212, 213, 214, 215 and pharmaceutically acceptable salts and complexes thereof .
  • the compound is selected from the group consisting of Compound 157, 158, 159, 163, 164, 166, 167, 168, 169, 170, 171, 181, 185, 186, and pharmaceutically acceptable salts and complexes thereof. These compounds have an IC 50 ⁇ 10 ⁇ M at an NMDA receptor. In more preferred aspects, the compound is selected from the group consisting of Compound 157, 158, 159, 163, 164, 167, 168, 169, 170, 171, 181, 185, 186, and pharmaceutically acceptable salts and complexes thereof. These compounds have an IC 50 ⁇ 2.5 ⁇ M at an NMDA receptor.
  • the compound is selected from the group consisting of Compound 157, 158, 159, 163, 164, 167, 168, 169, 170, 171, 181, 186, and pharmaceutically acceptable salts and complexes thereof. These compounds have an IC 50 ⁇ 0.5 ⁇ M at an NMDA receptor.
  • composition of matter aspect of the present invention are known compounds whose chemical structures are covered by the generic formulae presented above.
  • compositions useful for treating a patient having a neurological disease or disorder are provided in a pharmaceutically acceptable carrier and appropriate dose.
  • the pharmaceutical compositions may be in the form of pharmaceutically acceptable salts and complexes, as is known to those skilled in the art.
  • compositions comprise the compounds of Formulas I-IX and all preferred aspects of Formulas I-IX as set out above.
  • Preferred pharmaceutical compositions comprise Compounds 19 - 215.
  • the compound has an IC 50 ; 10 ⁇ M at an NMDA receptor. More preferably the compound has an IC S0 ⁇ ; 5 ⁇ M, more preferably ⁇ 2.5 ⁇ M, and most preferably ⁇ 0.5 ⁇ M at an NMDA receptor.
  • the pharmaceutical composition comprises a compound selected from the group consisting of Compound 20, 21, 22, 23, 24, 25, 27, 28, 29, 30, 31, 32, 33, 34, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 75, 76, 77, 78, 79, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 100, 101, 102, 103, 105, 106, 107, 108, 109, 111, 114, 115, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126
  • the compound is selected from the group consisting of 21, 22, 23, 24, 25, 26, 27, 28, 29, 33, 34, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 69, 76, 78, 79, 82, 83, 84, 88, 89, 90, 92, 93, 94, 95, 96, 98, 101, 102, 103, 105, 107, 108, 109, 111, 115, 116, 118, 119, 120, 121, 122, 124, 125, 126, 127, 129, 130, 131, 134, 135, 136, 137, 138 (potential prodrug) , 139, 141, 142
  • the compound is selected from the group consisting of 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 69, 76, 82, 83, 88, 89, 90, 92, 93, 94, 95, 96, 101, 102, 103, 105, 109, 111, 115, 118, 119, 120, 121, 122, 125, 126, 127, 129, 130, 131, 135, 136, 137, 138, 139, 142, 144, 145, 148, 149, and 150.
  • the pharmaceutical composition comprises a compound selected from the group consisting of Compound 20, 21, 22, 23, 24, 25, 27, 28, 29, 30, 31, 32, 33, 34, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66 , 69, 70, 75, 76, 81, 82, 83, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 100, 101, 102, 103, 105, 106, 108, 109, 111, 115, 118, 119, 120, 121, 122, 125, 126, 127, 128, 129, 130, 131, 132, 133, 135, 136, 137, 138 (potential prodrug) , 139, 142,
  • the compound is selected from the group consisting of 21, 22, 23, 24, 25, 27, 28, 29, 33, 34, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 69, 76, 82, 83, 88, 89, 90, 92, 93, 94, 95, 96, 101, 102, 103, 105, 108, 109, 111, 115, 118, 119, 120, 121, 122, 125, 126, 127, 129, 130, 131, 135, 136, 137, 138 (potential prodrug) , 139, 142, 144, 145, 148, 149, and 150.
  • the pharmaceutical composition comprises a compound is selected from the group consisting of Compound 20, 21, 22, 23, 24, 25, 27, 28, 30, 31, 32, 33, 38, 39, 43, 44, 46, 47, 49, 50, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 69, 82, 83, 89, 90, 91, 93, 94, 95, 96, 97, 103, 111, 118, 119, 120, 122, 126, 135, 136, 137, 138 (potential prodrug) , 142, 144, 145, 148, 149, and 150.
  • These compounds have an IC S0 _ 0.5 ⁇ M at an NMDA receptor.
  • the compound is selected from the group consisting of 21, 22, 23, 24, 25, 27, 28, 33, 38, 39, 43, 44, 46, 47, 49, 50, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 69, 82, 83, 89, 90, 93, 94, 95, 96, 103, 111, 118, 119, 120, 122, 126, 135, 136, 137, 138 (potential prodrug) , 142, 144, 145, 148, 149, and 150.
  • the pharmaceutical composition comprises a compound selected from the group consisting of Compound 20, 24, 25, 33,
  • the compound is selected from the group consisting of Compound 24, 25, 33, 50, 60, 66, 69, 103, 111, 118, 119, 120, 122, 136, 137, 138, 142, 144, 145, 148, 149, and 150.
  • the pharmaceutical composition comprises a compound selected from the group consisting of Compound 20, 33, 50, 60, 119, and 144.
  • the compound is selected from the group consisting of 33, 50, 60, 119, and 144.
  • the pharmaceutical composition comprises a compound selected from the group consisting of compound 151, 152, 153, 154, 155, 157,
  • the pharmaceutical composition comprises a compound which is selected from the group consisting of Compound 157, 158, 159, 163, 164, 166, 167, 168, 169, 170, 171, 181, 185, 186, and pharmaceutically acceptable salts and complexes thereof, and a pharmaceutically acceptable carrier.
  • These compounds have an IC S0 ⁇ 10 ⁇ M at an NMDA receptor.
  • the pharmaceutical composition comprises a compound which is selected from the group consisting of Compound 157, 158, 159, 163, 164, 166, 167, 168, 169, 170, 171, 181, 185, 186, and pharmaceutically acceptable salts and complexes thereof, and a pharmaceutically acceptable carrier. These compounds have an IC 50 ⁇ 2.5 ⁇ M at an NMDA receptor.
  • the pharmaceutical composition comprises a compound which is selected from the group consisting of Compound 157, 158, 159, 163, 164, 167, 168, 169, 170, 171, 181, 186, and pharmaceutically acceptable salts and complexes thereof, and a pharmaceutically acceptable carrier. These compounds have an IC 50 ⁇ 0.5 ⁇ M at an NMDA receptor.
  • Structural modifications can be made to compounds such as 20 or 60 which do not add materially to the structure-activity relationships (SAR) illustrated here.
  • successful bioisosteric replacement or substitution of optionally substituted phenyl groups can be accomplished with other lipophilic or semi-polar aromatic (e.g., naphthyl, naphthoxy, benzyl, phenoxy, phenylthio) , aliphatic (alkyl, e.g., isopropyl) , cycloaliphatic (cycloalkyl, e.g., cyclohexyl) , heterocyclic [e.g., pyridyl, f ranyl, thiofuranyl (thiophenyl) ] , or other functional groups or systems, as is well known in the art, will afford clinically useful compounds (structural homologs, analogs, and/or congeners) with similar biopharmaceutical properties and
  • NMDA receptor-active compounds with similarly useful biopharmaceutical properties, such as Compound 88 (a modified "classical H x -antlhistamme-type" structure) , which can be further optimized for activity at the NMDA receptor by preparing, e.g., the corresponding compound(s) containing, e.g., (bis) (3- fluorophenyl) group(s) , as taught by the present invention.
  • the propyl backbone of compounds such as 20 and 60 may also be modified successfully by the incorporation of ring systems (as in Compounds 102 and 111) and/or unsaturation (e.g., a double bond, as in Compounds 81, 106, 109, and 139) to afford further clinically useful NMDA receptor-active compounds of the present invention ( cf. compounds cited above) .
  • the invention features a method for making a therapeutic agent comprising the steps of screening for said agent by determining whether said agent is active on a receptor-operated calcium channel, and synthesizing said therapeutic agent in an amount sufficient to provide said agent in a therapeutically effective amount to a patient.
  • Said screening may be performed by methods known to those of ordinary skill in the art, and may, for example be performed by the methods set out herein. Those skilled in the art are also familiar with methods used to synthesize therapeutic agents in amounts sufficient to be provided in a therapeutically effective amount.
  • said receptor-operated calcium channel is an NMDA receptor.
  • said method further comprises the step of adding a pharmaceutically acceptable carrier to said agent.
  • said therapeutic agent comprises a compound of Formula I , as set out herein.
  • said therapeutic agent comprises a compound of Formula II, III, IV, V, VI, VII, VIII, or IX, as set out herein.
  • said therapeutic agent comprises a compound having a structure selected from the group consisting of Formulas I-IX, and all preferred aspects of said formulas as set out herein.
  • said therapeutic agent is selected from the group consisting of Compounds 19-215.
  • said therapeutic agent is provided to a patient having a neurological disease or disorder.
  • said screening comprises the step of identifying a compound which binds to said receptor-operated calcium channel at a site bound by one of the arylalkylamines Compound 1, Compound 2, and Compound 3.
  • Radioligand binding techniques a radiolabeled arylalkylamine binding assay
  • a radiolabeled arylalkylamine binding assay a radiolabeled arylalkylamine binding assay
  • Data from such radioligand binding studies will also confirm that said compounds do not inhibit [ 3 H] arylalkylamine binding via an action at the known sites on receptor-operated Ca 2* channels (such as the glutamate binding site, glycine binding site, MK-801 binding site, Zn 2+ binding site, Mg 2+ binding site, sigma binding site, or polyamine binding site on the
  • NMDA receptor-ionophore complex NMDA receptor-ionophore complex
  • an arylalkylamine affinity column can be prepared, and solubilized membranes from cells or tissues containing the arylalkylamine receptor passed over the column.
  • the receptor molecules bind to the column and are thus isolated. Partial amino acid sequence information is then obtained which allows for the isolation of the gene encoding the receptor.
  • cDNA expression libraries are prepared and subfractions of the library are tested for their ability to impart arylalkylamine receptors on cells which do not normally express such receptors (e.g., CHO cells, mouse L cells, HEK 293 cells, or Xenopus oocytes) . In this way, the library fraction containing the clone encoding the receptor is identified. Sequential subfractionation of active library fractions and assay eventually results in a single clone encoding the arylalkylamine receptor.
  • hybrid-arrest or hybrid-depletion cloning can be used.
  • Xenopus oocytes are injected with mRNA from an appropriate tissue or cell source (e.g., human brain tissue) .
  • Expression of the arylalkylamine receptor is detected as, for example, an NMDA- or glutamate-stimulated influx of calcium which can be blocked by Compound 1 , Compound 2 or Compound 3.
  • cDNA clones are tested for their ability to block expression of this receptor when cDNA or cRNA are hybridized to the mRNA of choice, prior to injection into Xenopus oocytes. The clone responsible for this effect is then isolated by the process described above.
  • the receptor gene is isolated, standard techniques are used to identify the polypeptide or portion(s) thereof which is (are) sufficient for binding arylalkylamines (the arylalkylamine binding domain[s] ) . Further, using standard procedures, the entire receptor or arylalkylamine binding domain(s) can be expressed by recombinant technology. Said receptor or binding domain(s) can be isolated and used as a biochemical reagent such that, rather than using a competitive assay exemplified below, a simple direct binding assay can be used. That is, a screen is set up for compounds which bind at the novel arylalkylamine receptor. In this way large numbers of compounds can be simultaneously screened, e.g., by passage through a column containing the novel arylalkylamine receptor or arylalkylamine binding domain, and analysis performed on compounds which bind to the column.
  • NMDA, AMPA or nicotinic cholinergic receptors NMDA, AMPA or nicotinic cholinergic receptors
  • patch clamp electrophysiological techniques Specifically, arylalkyl-amine analogs can be rapidly screened for potency at cloned and expressed subunits of the above-mentioned receptor-ionophore complexes.
  • Site-directed mutagenesis can be utilized in an effort to identify which amino acid residues may be important in determining arylalkylamine potency.
  • Desired properties of a drug include: high affinity and selectivity for receptor-operated Ca 2 * channels, such as those present in NMDA, AMPA and nicotinic cholinergic receptor-ionophore complexes (compared to responses mediated via other neurotransmitter receptors, neurotransmitter receptor-operated ion channels, or voltage-dependent ion channels) and a noncompetitive antagonism of said receptor-operated Ca 2 * channels.
  • the NMDA receptor-ionophore complex is utilized as an example of a receptor-operated Ca 2* channel.
  • Activation of the NMDA receptor opens a cation-selective channel that allows the influx of extracellular Ca 2 * and Na*, resulting in increases in [Ca 2 *] x and depolarization of the cell membrane.
  • Measurements of [Ca 2 *] were used as primary assays for detecting the activity of arylalkylamine compounds on NMDA receptors.
  • Purified arylalkylamines, synthetic aryl-alkylamines, and synthetic analogs of arylalkylamines were examined for activity in in vi tro assays capable of measuring glutamate receptor activity. Selected for detailed study were the arylalkylamines present in the venom of various spider species.
  • arylalkylamines present in these venoms are structurally distinct but have the basic structure of the class represented by Compounds 1 through 3.
  • Other more simplified synthetic analogs generally consist of suitably substituted aromatic chro ophoric groups attached to an alkyl (poly) amine moiety (see Compounds 19 through 215 below) .
  • a primary assay that provides a functional index of glutamate receptor activity and that allows high-throughput screening was developed.
  • Primary cultures of rat cerebellar granule cells loaded with the fluorimetric indicator fura-2 were used to measure changes in [Ca 2 *] t elicited by NMDA and its coagonist glycine.
  • This assay provides an extremely sensitive and precise index of NMDA receptor activity. Increases in [Ca 2 *] j, evoked by NMDA are dependent on the presence of glycine, and are blocked by extracellular Mg 2 * or antagonists acting at the glutamate, glycine, or MK-801 binding sites.
  • Example 1 Potent noncompetitive inhibition of NMDA receptor function
  • arylalkylamines tested blocked increases in [Ca 2 *] in cerebellar granule cells elicited by NMDA/glycine.
  • the inhibitory effects of the arylalkylamines were not overcome by increasing the concentrations of NMDA or glycine. That is, no change was observed in the EC 50 for either NMDA or glycine.
  • the arylalkylamines are thus noncompetitive antagonists at the NMDA receptor-ionophore complex, and act neither at the glutamate nor the glycine binding sites .
  • Measurements of [Ca 2 *] ⁇ in cerebellar granule cells can also be used to monitor activation of the native kainate or AMPA receptors present in this tissue. Although the increases in [Ca 2 *] ⁇ evoked by these agonists are of a lesser magnitude than those evoked by NMDA/glycine, such responses are robust and can be used to precisely assess the specificity of action of arylalkylamines on pharmacologically defined glutamate receptor subtypes. Comparative measurements of [Ca 2 *] x revealed a clear distinction in the receptor selectivity of the arylalkylamines.
  • arylalkylamines within the two structural classes defined by Compound 1 and by Compound 2 were found to inhibit preferentially responses evoked by NMDA (showing about a 100-fold difference in potency) .
  • arylalkylamines such as Compound 1 and Compound 2 are potent and selective inhibitors of NMDA receptor-mediated responses in cerebellar granule cells.
  • arylalkylamines could be distinguished from both Mg 2 * and MK-801, especially with respect to the voltage-dependence of their onset of action and reversibility of effect.
  • arylalkylamines such as Compound 1 and Compound 2 have a unique site of action. Although they act like MK-801 in some respects (noncompetitive open-channel blockade, discussed above) , they fail to displace [ 3 H]MK-801 binding at concentrations that completely block NMDA receptor-mediated responses. Assays such as these also demonstrate that the arylalkylamines do not bind with high affinity to the known MK-801, Mg 2* , or polyamine binding sites on the NMDA receptor-ionophore complex.
  • Glutamate- ediated transmission at synapses of Schaffer collateral fibers and CAl pyramidal cells was measured in slices of rat brain containing the hippocampus. This assay measures electrophysiologically the postsynaptic depolarization caused by the presynaptic release of glutamate, and can readily distinguish synaptic transmission mediated by NMDA or AMPA receptors.
  • Arylalkylamines like Compound 1, Compound 2 and Compound 3 were again found to exert preferential inhibitory effects on NMDA receptor-mediated responses, and depressed responses mediated by AMPA receptors only at much higher concentrations.
  • Compound 1 had an IC 50 for the NMDA receptor-mediated response of 20 ⁇ M, but an IC 50 for the AMPA receptor-mediated response of 647 ⁇ .
  • arylalkylamines can selectively inhibit synaptic transmission mediated by NMDA receptors.
  • Other naturally occurring arylalkylamines present in the venom of Agelenopsis aperta likewise exert potent and selective inhibitory effects on NMDA receptor-mediated responses in the rat hippocampus.
  • Desired properties of a neuroprotectant drug include the following.
  • the drug can be administered by oral or injectable routes (i.e., it is not significantly broken down in the stomach, intestine or vascular system and thus reaches the tissues to be treated in a therapeutically effective amount) .
  • Such drugs are easily tested in rodents to determine their bioavailability.
  • the drug exhibits neuroprotectant activity (i.e. , efficacy) when given after an ischemic insult (stroke, asphyxia) or traumatic injury (head trauma, spinal cord injury) .
  • the drug is devoid of or has minimal side effects such as impairment of cognition, disruption of motor performance, sedation or hyperexcitability, neuronal vacuolization, cardiovascular activity, PCP-like abuse potential, or PCP-like psychotomimetic activity.
  • NMDA and AMPA receptors play a major role in mediating the neuronal degeneration following a stroke and other ischemic/hypoxic events (Choi, Glutamate neurotoxicity and diseases of the nervous system. Neuron 1: 623, 1988) . Most of this evidence is based on the ability of competitive or noncompe itive antagonists of the NMDA or AMPA receptor to effectively block neuronal cell death in both in vi tro and in vi vo models of stroke. Compound 1, Compound 2 and Compound 4 were therefore examined for neuroprotectant effects in standard assays designed to detect such activity.
  • LDH lactate dehydrogenase
  • the effective concentrations of the arylalkylamines are higher than those of other noncompetitive NMDA receptor antagonists, but similar to those of competitive antagonists.
  • the effective concentrations of NMDA receptor antagonists vary depending on the particular experimental conditions and the type of cell studied (cortical, hippocampal, striatal) . This neuroprotectant effect likely results from the ability of these compounds to block the influx of extracellular Ca 2 * triggered by the NMDA receptor. More rigorous testing to determine potential therapeutic efficacy involved in vivo stroke models. In these models, the blood supply is temporarily blocked by clamping the main arteries to the brain. Two in vivo models of this sort were used to determine the ability of Compound 1, Compound 2 and Compound 4 to prevent neuronal cell loss.
  • the first assay was the bilateral common carotid artery occlusion model of forebrain ischemia performed in the gerbil (Karpiak et al . , Animal models for the study of drugs in ischemic stroke. Ann. .Rev. Pharmacol . Toxicol . 29: 403, 1989; Ginsberg and Busto, Rodent models of cerebral ischemia. Stroke 20: 1627, 1989) . Blood flow to the brain was interrupted for 7 minutes by clamping the carotid arteries. The test compounds were administered as a single dose given intraperitoneally (i.p.) 30 minutes after reinstating blood flow. During the course of these experiments, the core body temperature of the animals was maintained at
  • Example 8 Middle cerebral artery occlusion
  • the middle cerebral artery model of stroke performed in the rat (Karpiak et al . , Animal models for the study of drugs in ischemic stroke. Ann. Rev. Pharmacol . Toxicol . 29: 403, 1989; Ginsberg and Busto, Rodent models of cerebral ischemia. Stroke 20: 1627, 1989) is different from the gerbil model because it results in a more restricted brain infarct, and thereby approximates a different kind of stroke (focal thrombotic stroke) .
  • one cerebral artery was permanently occluded by surgical ligation.
  • the test compounds were administered 30 minutes after the occlusion by a single intraperitoneal (i.p.) injection.
  • the gerbil assay is a model for transient global cerebral ischemia and hypoxia such as cardiac arrest or perinatal hypoxia.
  • the rat assays are models of permanent and temporary focal cerebral ischemia.
  • the finding that Compound 1 and Compound 4 are neuroprotective in the permanent focal stroke models is surprising because the accessibility of the drug to the site of infarction is limited to the penumbral region which generally is not large. Nonetheless, Compound 1 and Compound 4 significantly (p ⁇ 0.05) limited the extent of damage.
  • the compounds are effective when administered after the ischemic event. This is important because there is believed to be a "window of opportunity" following an infarct during which drugs may effectively halt necrotic damage.
  • Desired properties of an anticonvulsant drug include: the drug can be administered by oral or injectable routes, the drug exhibits effective anticonvulsant activity against several seizure types, including, but not limited to, simple partial seizures, complex partial seizures, status epilepticus, and trauma-induced seizures such as occur following head injury, including head surgery; and the drug is devoid of or has minimal side effects such as impairment of cognition, disruption of motor performance, sedation or hyperexcitability, neuronal vacuolization, cardiovascular activity, PCP-like abuse potential, or PCP-like psychotomimetic activity.
  • the drug can be administered by oral or injectable routes, the drug exhibits effective anticonvulsant activity against several seizure types, including, but not limited to, simple partial seizures, complex partial seizures, status epilepticus, and trauma-induced seizures such as occur following head injury, including head surgery; and the drug is devoid of or has minimal side effects such as impairment of cognition, disruption of motor performance, sedation or hyperexcitability, neuronal vacuo
  • Glutamate is the major excitatory transmitter in the brain, and thus may play a major role in seizure activity, and contribute to the pathogenesis of epilepsy.
  • Much of the evidence favoring a major role for glutamate receptors in epilepsy derives from pharmacological studies demonstrating that glutamate receptor agonists elicit seizures, and that NMDA and AMPA receptor antagonists are effective anticonvulsants when administered in vivo .
  • arylalkylamines In initial studies, the ability of arylalkylamines to block seizures induced by kainate, picrotoxin or bicuculline were examined. Each of these convulsants acts through a different mechanism and seizures elicited by kainate are qualitatively different from those elicited by picrotoxin or bicuculline. In these experiments, a fraction of Agelenopsis aperta venom containing several arylalkylamine toxins was administered intravenously (iv) 5 min before picrotoxin or bicuculline, and 5 min after kainate administration. The arylalkylamines diminished the seizures induced by all three of these agents.
  • Example 10 Seizure stimuli Three different seizure-inducing test paradigms were used initially in this second group of studies and arylalkylamines such as Compound 1 proved to be effective anticonvulsants in two such paradigms.
  • the first two models used DBA/2 mice which are prone to audiogenic seizures. Seizures were elicited by sound (bell tone at 109 dBs) or the intraperitoneal (ip) administration of NMDA (56 mg/kg) .
  • the test substances were administered 15-30 min before the convulsant stimulus. The number of clonic seizures was recorded for 1 min following the audiogenic stimulus or for 15 min following the administration of NMDA.
  • Compound 1 Compound 2, and several other arylalkylamines such as Compound 3 and Compound 4 depressed seizures evoked by either stimulus.
  • Compound 2 had an ED 50 of 0.13 mg/kg s.c. for audiogenic stimulus and 0.083 mg/kg s.c. for NMDA stimulus.
  • the EC 50 for Compound 4 in the audiogenic seizure model (0.08 mg/kg) approached that for MK-801 (0.02 mg/kg) .
  • neither Compound 1 nor Compound 2 was effective at doses up to 50 mg/kg s.c. in reducing seizures in CF-1 mice elicited by i.p. NMDA.
  • Compound 1 and Compound 4 were found to prevent seizures induced by sound in another genetically susceptible mouse model of reflex epilepsy (Frings mice) following intraperitoneal injection with IC 50 values of 14.3 mg/kg and -15 mg/kg, respectively. These compounds were considerably more potent against audiogenic seizures in Frings mice following intracerebroventricular (i.e.v.) injection, with IC 50 values of 0.63 ⁇ g (Compound 1) and 4.77 ⁇ g (Compound 4) . Compound 1 was also found to be effective against seizures elicited by maximal electroshock in CF1 mice at a dose of 4 ⁇ g i.e.v.
  • Desired properties of an analgesic drug include: the drug can be administered by oral or injectable routes, the drug exhibits analgesic activity, the drug is devoid of or has minimal side effects such as impairment of cognition, disruption of motor performance, sedation or hyperexcitability, neuronal vacuolization, cardiovascular activity, PCP-like abuse potential, or PCP-like psychotomimetic activity.
  • Compound 1 Compound 1 and Compound 3 alleviate visceral pain.
  • Compound 1 was tested for analgesic activity in an additional assay.
  • mice were administered test substances s.c. 30 min before being placed on a hot plate (50°C) .
  • the time taken to lick the feet or jump off the plate is an index of analgesic activity, and effective analgesics increase the latency to licking or jumping.
  • Morphine (5.6 mg/kg) increased the latency to jump by 765%.
  • Compound 1 was likewise effective in this assay and, at doses of 4 and 32 mg/kg, increased the latency to foot licking by 136% and the latency to jumping by 360%, respectively. It is noteworthy that the analgesic effects of
  • Compound 1 and Compound 4 were demonstrated to possess significant analgesic activity in rats when administered by the intrathecal (i.th.) route.
  • a 52°C hot plate was used as the nociceptive stimulus.
  • Compound 1 (0.3 - 3 nmol) and Compound 4 (0.3 - 3 nmol) produced dose- and time-dependent antinociceptive effects; these arylalkylamines were similar to morphine (0.3 - 3 nmol) in terms of potency and efficacy.
  • the NMDA receptor antagonist, MK-801 was ineffective in this assay (3-30 nmol) .
  • Example 13 Tail flick test In this standard assay, the thermal nociceptive stimulus was 52°C warm water with the latency to tail flick or withdrawal taken as the endpoint .
  • Compound 1 (0.3 - 3 nmol) and Compound 4 (0.3 - 3 nmol) produced a dose- and time-dependent analgesic effect following i.th. administration.
  • These arylalkylamines were similar to morphine (0.3 - 3 nmol) in terms of potency and efficacy.
  • the NMDA receptor antagonist, MK-801 was ineffective in this assay (3-30 nmol) .
  • This analgesic profile of activity of the arylalkylamines is similar to that seen with post-formalin administration of morphine (1 - 10 nmol) ; post-formalin administration of MK-801 (1 - 30 nmol) , however, failed to affect late-phase flinching.
  • arylalkylamines such as Compound 1 and Compound 4 have significant analgesic activity several rodent models of acute pain.
  • the formalin assay additionally demonstrates that arylalkylamines are effective in an animal model of chronic pain.
  • the arylalkylamines possess significant analgesic activity when administered after the formalin stimulus. This profile of activity clearly distinguishes the arylalkylamines from standard NMDA receptor antagonists such as MK-801.
  • NMDA receptors Given the important role NMDA receptors play in diverse brain functions, it is not surprising to find that antagonists of this receptor are typically associated with certain unwelcome side effects. In fact, it is this property that provides the major obstacle to developing therapies that target NMDA receptors.
  • the principal side effects which characterize both competitive and noncompetitive antagonists, are a PCP-like psychotomimetic activity, impairment of motor performance, sedation or hyperexcitability, impairment of cognitive abilities, neuronal vacuolization, or cardiovascular effects (Willetts et al . , The behavioral pharmacology of NMDA receptor antagonists. Trends Pharmacol . Sci . 11: 423, 1990; Olney et al .
  • arylalkylamines were examined in animal models that index motor impairment, sedation and psychotomimetic activity as well as both in vi tro and in vivo models of learning and memory.
  • both competitive and noncompetitive antagonists of the NMDA receptor produce a PCP-like stereotypic behavior characterized by hyperactivity, head-weaving, and ataxia (Willetts et al . , The behavioral pharmacology of NMDA receptor antagonists. Trends Pharmacol . Sci . 11: 423, 1990; Snell and Johnson, In: Exci ta tory Amino Acids in Heal th and Disease, John Wiley & Sons, p. 261, 1988) .
  • the first assay simply monitors locomotor activity during the first hour following peripheral
  • Example 16 Motor impairment
  • Compound 1 was examined in the inverted grid assay.
  • animals are placed on a wire-holed grid suspended from a rotating metal bar which can be inverted. The animals are then scored for their ability to climb to the top or hang on to the grid. Animals with severe motor impairment fall off the grid.
  • This assay provides an index of "behavioral disruption" that may result from ataxia, loss of the righting reflex, sedation, or muscle relaxation.
  • Compound 1, administered at 32 mg/kg s.c did not lessen the ability of DBA/2 mice to right themselves when the grid was inverted (p > 0.05) .
  • Compound 2 was likewise without effect (p > 0.05) on motor performance in DBA/2 mice when administered at a dose of 20 mg/kg s.c. These doses are considerably higher than those required to prevent sound-induced seizures in DBA/2 mice (see Example 10 above) .
  • the second assay of acute motor impairment was the rotorod assay. In this assay, Frings and CF1 mice were injected with test compound and placed on a knurled rod which rotated at a speed of 6 rpm. The ability of the mice to maintain equilibrium for long periods of time was determined; those mice that were unable to maintain equilibrium on the rotorod for 1 min in each of 3 trials were considered impaired.
  • Compound 1 produced acute motor impairment in Frings mice with a TD 50 (that dose which produced motor toxicity in 50% of the test animals) of 16.8 mg/kg i.p. This dose is similar to that which prevents sound-induced seizures in Frings mice (see Example 10 above) .
  • TD 50 that dose which produced motor toxicity in 50% of the test animals
  • Compound 1 is administered i.e.v. In this case, no apparent motor toxicity was evident until the dose of Compound 1 exceeded 1.56 ⁇ g i.e.v. (>2 times the ED 50 of 0.63 ⁇ g) .
  • motor impairment in CF1 mice was noted with Compound 1 following i.e.v. administration of 4 ⁇ g.
  • Compound 4 Compound 4
  • Compound 9 Compound 12 and
  • Compound 14 were administered to Frings mice by i.e.v. injection, and acute motor impairment was measured.
  • the TD 50 values for Compounds 4, 9, 12 and 14 were 8-16 ⁇ g, 14.8 ⁇ g, 30.2 ⁇ g and 30.8 ⁇ g, respectively. These TD 50 values were 2-3 times higher than the effective IC 50 values for anticonvulsant potency (see Example 10 above) ; a clear separation between effective and toxic doses was noted.
  • Example 17 PCP discrimination
  • rats who have been trained to lever press for food reinforcement must select which of two levers in their cages is correct. The only stimulus they have for selecting the correct lever is their ability to detect whether they received a PCP or vehicle injection. After about two months of training, rats become very good at discriminating PCP from vehicle injections and can then be tested with other drugs to determine if they are discriminated as PCP. When tested in this procedure, other drugs which are known to produce a PCP-like intoxication substitute for PCP.
  • These drugs include various PCP analogs such as ketamine and the noncompetitive NMDA receptor antagonist, MK-801.
  • Compound 1 (1 - 30 mg/kg i.p.) did not substitute for PCP, and thus was completely devoid of PCP-like discriminative stimulus effects. At 30 mg/kg i.p., only 1 of the 7 animals tested responded at all on either lever. It is thus clear that a behaviorally effective dosage range of Compound 1 was evaluated. As the ability of test compounds to produce PCP-like effects in rats is believed to be predictive of their ability to produce PCP-like psychotomimetic activity and abuse liability in humans, these results strongly suggest that the arylalkylamines such as Compound 1 will lack such deleterious side effects in man.
  • vacuolization a neurotoxic effect termed neuronal vacuolization.
  • vacuoles are found in particular central neurons, especially those in the cingulate cortex and retrosplenial cortex. No such vacuolization was present in rats treated with Compound 1 at the single high dose of 100 mg/kg i.p.
  • LTP long-term potentiation
  • Arylalkylamines are the first, and at present the only, class of compounds shown to be selective and potent antagonists of the NMDA receptor that do not block the induction of LTP. This likely reflects the novel mechanism and site of action of arylalkylamines and suggests that drugs which target the novel site on the NMDA receptor will similarly lack effects on LTP. As LTP is the primary cellular model for learning and memory in the mammalian CNS, it additionally suggests that such drugs will lack deleterious effects on cognitive performance.
  • Example 20 Learning tests Preliminary experiments using one of the more potent synthetic arylalkylamine analogs, Compound 3, in an m vi vo learning paradigm demonstrate that these drugs lack effects on cognitive performance.
  • rats were trained to alternate turning in a T maze for a food reward.
  • MK-801 was included for comparison. Test compounds were administered i.p. 15 min before testing Control animals made the correct choice about 80% of the time. Increasing doses of MK-801 progressively decreased the number of correct choices and this decrement in behavior was accompanied by hyperactivity. In contrast, Compound 3 did not impair the ability of the animals to make the correct choices (p > 0.05) . At the highest doses tested, Compound 3 caused some decrease in locomotor activity, exactly the opposite effect observed with MK-801.
  • Compound 3 on the previous day made the first choice correctly considerably more often. Unlike control animals then, the animals treated with Compound 3 behaved as if they remembered the last choice of the previous day.
  • arylalkylamines are quite potent inhibitors of voltage-sensitive Ca 2 * channels, specifically those sensitive to inhibition by dihydropyridines (L-type channels) .
  • Such effects on vascular smooth muscle would be expected to dilate blood vessels and cause a drop in blood pressure, thus producing hypotension.
  • Arylalkylamines are not, however, indiscriminate blockers of voltage-sensitive Ca 2 * channels. They do not, for example, affect voltage-sensitive Ca 2 * channels in cerebellar Purkm ⁇ e cells (P-type channels) or those channels thought to be involved in neurotransmitter release (N-channels) .
  • the arylalkylamines that do block voltage-sensitive Ca 2 * channels appear to target specifically L-type Ca 2* channels.
  • there is a high degree of structural specificity in this effect For example, one arylalkylamine is 57 times more potent than another arylalkylamine m blocking Ca 2* influx through L-type channels, where the only structural difference between the compounds is the presence or absence of a hydroxyl group.
  • Example 22 In vivo cardiovascular studies
  • the arylalkylamines Compound 1 and Compound 2 produce moderate drops (20-40 mm Hg) in mean arterial blood pressure (MABP) in anesthetized rats at doses which are effective m the in vivo stroke models (10-30 mg/kg s.c) .
  • MABP mean arterial blood pressure
  • the hypotensive effect of Compound 4 has been evaluated in greater detail.
  • Compound 4 elicited a marked drop (40 mm Hg) in mean arterial pressure which persisted for approximately 90-120 mm when administered at the dose of 10 mg/kg i.p.; it was in this same group of rats that Compound 4 afforded significant neuroprotection in the suture model of middle cerebral artery occlusion (see Example 8 above) .
  • Compounds 19 - 215 had high potencies against NMDA-induced increases in [Ca 2 *] ,_ in rat cerebellar granule cells grown in culture (Table 1) .
  • the inhibitory effect of Compound 19 on responses to NMDA was noncompetitive.
  • Compounds 19 - 215 inhibited [ 3 H]MK-801 binding in membranes prepared from rat hippocampal and cortical tissue (Table 1) .
  • Compound 60 possessed the following additional biological activities: significant anticonvulsant activity against sound-induced seizures in a genetically susceptible mouse model of 'reflex epilepsy (Frings mice) following i.p.
  • arylalkylamines which have therapeutically useful properties as defined above, compounds can now be identified which act at the critical arylalkylamine binding site on receptor-operated Ca 2 * channels, such as those present within NMDA, AMPA and nicotinic cholinergic receptor-ionophore complexes.
  • Example 24 Radioligand binding in rat cortex or cerebellum.
  • the following assay can be utilized as a high throughput assay to screen product libraries (e.g., natural product libraries and compound files at major pharmaceutical companies) to identify new classes of compounds with activity at this unique arylalkylamine site. These new classes of compounds are then utilized as chemical lead structures for a drug development program targeting the arylalkylamine binding site on receptor-operated Ca 2 * channels.
  • product libraries e.g., natural product libraries and compound files at major pharmaceutical companies
  • These new classes of compounds are then utilized as chemical lead structures for a drug development program targeting the arylalkylamine binding site on receptor-operated Ca 2 * channels.
  • the compounds identified by this assay offer a novel therapeutic approach to treatment of neurological disorders or diseases. Examples of such compounds include those provided in the generic chemical formulae above.
  • Routine experiments can be performed to identify those compounds having the desired activities.
  • Rat brain membranes are prepared according to the method of Williams et al . (Effects of polyamines on the binding of [ 3 H]MK-801 to the NMDA receptor: Pharmacological evidence for the existence of a polyamine recognition site. Molec . Pharmacol . 36: 575, 1989) with the following alterations: Male Sprague-Dawley rats (Harlan Laboratories) weighing 100-200 g are sacrificed by decapitation. The cortex or cerebellum from 20 rats are cleaned and dissected. The resulting brain tissue is homogenized at 4°C with a polytron homogenizer at the lowest setting in 300 ml 0.32 M sucrose containing 5 mM K-EDTA (pH 7.0) .
  • the homogenate is centrifuged for 10 mm at 1,000 x g and the supernatant removed and centrifuged at 30,000 x g for 30 minutes.
  • the resulting pellet is resuspended in 250 ml 5 mM K-EDTA (pH 7.0) stirred on ice for 15 min, and then centrifuged at 30,000 x g for 30 minutes.
  • the pellet is resuspended in 300 ml 5 M K-EDTA (pH 7.0) and incubated at 32°C for 30 min. The suspension is then centrifuged at 100,000 x g for 30 min.
  • Membranes are washed by resuspension in 500 ml 5 mM K-EDTA (pH 7.0) , incubated at 32°C for 30 min, and centrifuged at 100,000 x g for 30 minutes. The wash procedure, including the 30 min incubation, is repeated. The final pellet is resuspended in 60 ml 5 mM K-EDTA (pH 7.0) and stored in aliquots at -80°C. The extensive washing procedure utilized in this assay was designed in an effort to minimize the concentrations of glutamate and glycine (co-agonists at the NMDA receptor-ionophore complex) present in the membrane preparation.
  • Nonspecific binding is determined in the presence of 100 ⁇ M nonradioactive arylalkylamine.
  • Duplicate samples are incubated at 0°C for 1 hour.
  • Assays are terminated by the addition of 3 ml of ice-cold buffer A, followed by filtration over glass-fiber filters (Schleicher & Schuell No. 30) that are presoaked in 0.33% polyethyleneimine (PEI) .
  • the filters are washed with another 3 x 3 ml of buffer A, and radioactivity is determined by scintillation counting at an efficiency of 35-40% for 3 H.
  • the amount of nonspecific binding of the [ 3 H] arylalkylamine to the filters is determined by passing 500 ⁇ l of buffer A containing various concentrations of [ 3 H] arylalkylamine through the presoaked glass-fiber filters.
  • the filters are washed with another 4 x 3 ml of buffer A, and radioactivity bound to the filters is determined by scintillation counting at an efficiency of 35-40% for 3 H.
  • radioactivity bound to the filters is determined by scintillation counting at an efficiency of 35-40% for 3 H.
  • filters that are not pretreated with 0.33% PEI it was found that 87% of the 3 H-ligand was bound to the filter. Presoaking with 0.33% PEI reduces the nonspecific binding to 0.5 - 1.0% of the total ligand added.
  • a saturation curve is constructed by resuspending SPMs in buffer A.
  • the assay buffer 500 ⁇ l
  • Concentrations of [ 3 H] arylalkylamine are used, ranging from 1.0 nM to 400 ⁇ M in half-log units.
  • a saturation curve is constructed from the data, and an apparent K D value and B m value determined by Scatchard analysis (Scatchard, The attractions of proteins for small molecules and ions. Ann. N. Y. Acad . Sci . 51: 660, 1949) .
  • the cooperativity of binding of the [ 3 H] arylalkylamine is determined by the construction of a Hill plot (Hill, A new mathematical treatment of changes of ionic concentrations in muscle and nerve under the action of electric currents, with a theory to their mode of excitation. J " . Physiol . 40: 190, 1910) .
  • the dependence of binding on protein (receptor) concentration is determined by resuspending SPMs m buffer A.
  • the assay buffer (500 ⁇ l) contains a concentration of [ 3 H] arylalkylamine equal to its K D value and increasing concentrations of protein. The specific binding of [ 3 H] arylalkylamine should be linearly related to the amount of protein (receptor) present.
  • the time course of ligand-receptor binding is determined by resuspending SPMs in buffer A.
  • the assay buffer (500 ⁇ l) contains a concentration of [ 3 H] arylalkylamine equal to its K D value and 100 ⁇ g of protein. Duplicate samples are incubated at 0°C for varying lengths of time; the time at which equilibrium is reached is determined, and this time point is routinely used in all subsequent assays .
  • the pharmacology of the binding site can be analyzed by competition experiments.
  • concentration of [ 3 H] arylalkylamine and the amount of protein are kept constant, while the concentration of test (competing) drug is varied.
  • This assay allows for the determination of an IC 50 and an apparent K D for the competing drug (Cheng and Prusoff, Relationship between the inhibition constant (KJ and the concentration of inhibitor which causes 50 percent inhibition (IC S0 ) of an enzymatic reaction. J. Biochem. Pharmacol . 22: 3099, 1973) .
  • the cooperativity of binding of the competing drug is determined by Hill plot analysis.
  • Specific binding of the [ 3 H] arylalkylamine represents binding to a novel site on receptor-operated Ca 2 * channels such as those present within NMDA-, AMPA- and nicotinic cholinergic receptor-ionophore complexes.
  • other arylalkylamines should compete with the binding of [ 3 H] arylalkylamine in a competitive fashion, and their potencies in this assay should correlate with their inhibitory potencies in a functional assay of receptor-operated Ca 2 * channel antagonism (e.g., inhibition of NMDA receptor-induced increases in [Ca 2 *] 1 in cultures of rat cerebellar granule cells) .
  • [ 3 H] arylalkylamine binding indicative of noncompetitive interactions, might be expected to occur.
  • MK-801 did not displace [ 3 H] arylalykylamine binding at concentrations up to 100 ⁇ M.
  • Example 25 Radioligand binding in cerebellar granule cells
  • Cultures are maintained in Eagles' medium (HyClone Laboratories) containing 25 mM KCI, 10% fetal calf serum (HyClone Laboratories) , 2 mM glutamine, 100 ⁇ g/ml gentamicin, 50 U/ml penicillin, and 50 ⁇ g/ml streptomycin at 37°C in a humid atmosphere of 5% C0 2 in air for 24 hr before the addition of cytosine arabinoside (10 ⁇ M, final) . No changes of culture medium are made until the cells are used for receptor binding studies 6-8 days after plating.
  • the reaction mixture consists of 200 ⁇ l of buffer A (20 mM K-HEPES, 1 mM K-EDTA, pH 7.0) in each well of the 24-well plate.
  • the [ 3 H] arylalkylamine is added to this reaction mixture.
  • Nonspecific binding is determined in the presence of 100 ⁇ M nonradioactive arylalkylamine.
  • Triplicate samples are incubated at 0°C for 1 hour. Assays are terminated by manually scraping the cells off the Aclar squares and placing them into polypropylene test tubes.
  • the membranes prepared from whole cells in this manner are suspended in 10 ml of ice-cold buffer A, and filtered over glass-fiber filters (Schleicher & Schuell No. 30) that are presoaked in 0.33% PEI.
  • the filters are washed with another 3 x 3 ml of buffer A, and radioactivity on the filters is determined by scintillation counting at an efficiency of 35-40% for 3 H.
  • the assay may be terminated by centrifugation rather than filtration in order to minimize nonspecific binding.
  • the binding assay allows for the determination of an IC S0 value and an apparent K D for the competing drug as described by Scatchard analysis (The attractions of proteins for small molecules and ions. Ann. N. Y. Acad . Sci . 51: 660, 1949) . Cooperativity of binding of the competing drug is determined by Hill plot analysis (A new mathematical treatment of changes of ionic concentrations in muscle and nerve under the action of electric currents, with a theory to their mode of excitation. J. Physiol . 40: 190, 1910) .
  • the specific binding of the [ 3 H] arylalkylamine represents binding to a novel site on receptor-operated calcium channels .
  • a rapid screening assay for useful compounds of this invention a cDNA or gene clone encoding the arylalkylamine binding site (receptor) from a suitable organism such as a human is obtained using standard procedures. Distinct fragments of the clone are expressed in an appropriate expression vector to produce the smallest polypeptide (s) obtainable from the receptor which retain the ability to bind Compound 1, Compound 2 or Compound 3. In this way, the polypeptide (s) which includes the novel arylalkylamine receptor for these compounds can be identified.
  • Such experiments can be facilitated by utilizing a stably transfected mammalian cell line (e.g., HEK 293 cells) expressing the arylalkylamine receptor.
  • the arylalkylamine receptor can be chemically reacted with chemically modified Compound 1, Compound 2 or Compound 3 in such a way that amino acid residues of the arylalkylamine receptor which contact (or are adjacent to) the selected compound are modified and thereby identifiable.
  • Compound 2 or Compound 3 and are sufficient for binding to said molecules can then be recomb antly expressed, as described above, using a standard expression vector(s) .
  • the recombinant polypeptide (s) having the desired binding properties can be bound to a solid phase support using standard chemical procedures.
  • This solid phase, or affinity matrix may then be contacted with Compound 1, Compound 2 or Compound 3 to demonstrate that those compounds can bind to the column, and to identify conditions by which the compounds may be removed from the solid phase.
  • This procedure may then be repeated using a large library of compounds to determine those compounds which are able to bind to the affinity matrix, and then can be released in a manner similar to Compound 1, Compound 2 or Compound 3.
  • alternative binding and release conditions may be utilized m order to obtain compounds capable of binding under conditions distinct from those used for arylalkylamine binding (e.g., conditions which better mimic physiological conditions encountered especially in pathological states) .
  • Those compounds which do bind can thus be selected from a very large collection of compounds present in a liquid medium or extract .
  • those compounds able to bind to the arylalkylamine binding polypeptide (s) described above are identified, those compounds can then be readily tested in the various assays described above to determine whether they, or simple derivatives thereof, are useful compounds for therapeutic treatment of neurological disorders and diseases described above.
  • native arylalkylamine receptor can be bound to a column or other solid phase support. Those compounds which are not competed off by reagents which bind other sites on the receptor can then be identified. Such compounds define novel binding sites on the receptor. Compounds which are competed off by other known compounds thus bind to known sites, or bind to novel sites which overlap known binding sites. Regardless, such compounds may be structurally distinct from known compounds and thus may define novel chemical classes of agonists or antagonist which may be useful as therapeutics. In summary, a competition assay can be used to identify useful compounds of this invention.
  • the following assay is performed for selected compounds identified in the above-mentioned radioligand binding assays as interacting in a highly potent and competitive fashion at the novel arylalkylamine binding site on receptor-operated Ca 2 * channels, such as those present in NMDA-, AMPA- or nicotinic cholinergic receptor-ionophore complexes.
  • This patch-clamp assay provides additional relevant data about the site and mechanism of action of said previously selected compounds.
  • the following pharmacological and physiological properties of the compounds interacting at the arylalkylamine binding site are determined, utilizing the NMDA receptor-ionophore complex as an example of receptor-operated Ca 2 * channels: potency and efficacy at blocking NMDA receptor-mediated ionic currents, the noncompetitive nature of block with respect to glutamate and glycine, use-dependence of action, voltage-dependence of action, both with respect to onset and reversal of blocking, the kinetics of blocking and unblocking (reversal) , and open-channel mechanism of blocking.
  • patch-clamp experiments can be performed on Xenopus oocytes or on a stably transfected mammalian cell line (e.g., HEK 293 cells) expressing specific subunits of receptor-operated Ca 2 * channels.
  • a stably transfected mammalian cell line e.g., HEK 293 cells
  • potency and efficacy at various glutamate receptor subtypes e.g., NMDARl, NMDAR2A through NMDAR2D, GluRl through GluR4
  • Further information regarding the site of action of the arylalkylamines on these glutamate receptor subtypes can be obtained by using site-directed mutagenesis.
  • Arylalkylamines such as Compound 1, Compound 2 and Compound 3 are synthesized by standard procedures (Jasys et al . , The total synthesis of argiotoxins 636, 659 and 673. Tetrahedron Lett. 29: 6223, 1988; Nason et al . , Synthesis of neurotoxic Nephila spider venoms: NSTX-3 and JSTX-3. Tetrahedron Let t . 30: 2337, 1989) .
  • Specific examples of syntheses of arylalkylamine analogs 4-18 are provided in co-pending application U.S. Serial No. 08/485,038, filed June 7, 1995, and co-pending International Patent Application No. PCT/US94/12293 , published as W095/21612, filed October 26, 1994, hereby incorporated by reference herein in their entirety.
  • Product 3 was synthesized by the catalytic reduction of 2 using Raney nickel in 95:5 EtOH:aqueous sodium hydroxide (2 Eq. ) under 60 psi hydrogen.
  • m/z (rel.
  • the absolute configuration of Compound 33 -HI was determined to be R by single-crystal (monoclinic colorless needle, 0.50 x 0.05 x 0.03 mm) X-ray diffraction analysis using a Siemens R3m/V diffractometer (3887 observed reflections) .
  • Triethyl phosphonoacetate (17.2 g, 76.8 mmol) was slowly added to a suspension of sodium hydride (3.07 g, 76.8 mmol) in N,N-dimethylformamide (350 ml) .
  • 3 ' -difluorobenzophenone (15.2 g, 69.8 mmol) was added to the solution and stirred an additional 18 hr.
  • the reaction mixture was quenched with water and partitioned between water and ether.
  • the combined organic layers were washed with brine and dried over anhydrous magnesium sulfate.
  • the solvent was evaporated in vacuo to give 19.7 g of ethyl 3 , 3-bis (3-fluorophenyl) acrylate as a yellow oil.
  • the ethyl ester A (19.2 g) was hydrolyzed by stirring for 6 days with 50 ml of 10 N sodium hydroxide. The reaction mixture was then diluted with 50 ml of water and acidified to pH 0 with concentrated HCI. The aqueous mixture was extracted 3 times with ether and the ether extracts dried over magnesium sulfate and evaporated to give 3 , 3-bis (3-fluorophenyl) propionic acid as a white powder.
  • Compounds 101 and 103 were synthesized from Compounds 25 and 24, respectively, by cleavage of their O-methyl ethers with borane tribromide in the normal manner.
  • a suspension containing magnesium turnings (0.95 g, 39.1 mmol) in 150 ml anhydrous diethyl ether was treated with l-bromo-3-fluorobenzene (6.85 g, 39.1 mmol) dropwise via syringe. After 1.5 hr the solution was transfered via cannula to a flask containing 3-chlorobenzaldehyde (5.0 g, 35.6 mmol) in 100 ml anhydrous diethyl ether at 0°C and stirred 2 hr. The reaction mixture was quenched with water and partitioned between water and ether.
  • the ketone B (1.3 g, 4.9 mmol) was added to a solution of methoxylamine hydrochloride (0.45 g, 5.38 mmol) and pyridine (0.44 ml, 5.38 mmol) in 30 ml of ethanol, and stirred overnight. The ethanol was then evaporated, and the residue taken up in ether and 10% HCI. The ether layer was separated, washed once with 10% HCI, dried over sodium sulfate and evaporated to give 1.4 g of the O-methyl oxime.
  • Compound 50 was also prepared using the chiral synthesis described below.
  • the reaction was cooled to -78°C in a dry ice/isopropanol bath and then a solution of benzyl crotonate (15.0 g, 85.2 mmol) in THF (100 ml) was added dropwise over a period of 45 mm.
  • the reaction was stirred at -78°C for 15 min, and then saturated ⁇ H 4 C1 (50 ml) was added.
  • the reaction mixture was then quickly transferred to a separatory funnel containing saturated NaCl (500 ml) and ether (200 ml) . The layers were separated and the aqueous layer extracted with ether (200 ml) .
  • Product B (20.02 g, 42.45 mmol, theoretical) was dissolved in acetic acid (120 ml) and sulfuric acid (30 ml) . The reaction was stirred at 90°C for 1 hr. The acetic acid was rotary evaporated giving a brown sludge. This material was placed in an ice bath and cold water (400 ml) was added. The product immediately precipitated. To the reaction was slowly added 10 N NaOH (150 ml) to neutral pH. Diethyl ether (200 ml) was added to this mixture. The mixture was shaken until there was no undissolved material.
  • Compound 51 was synthesized in a similar manner to Compound 50 utilizing N-benzyl - (R) - ⁇ - methylbenzylamme as a chiral starting material.
  • the alcohol A (8.4 g, 36.2 mmol) was stirred with manganese dioxide (12.6 g, 144.8 mmol) in 100 ml of dichloromethane for 4 days.
  • the reaction mixture was then diluted with ether and filtered through a 0.2 micron teflon membrane filter. The filtrate was concentrated to give 7.6 g of the ketone B.
  • the substituted acrylonitrile C was synthesized as described for product A in the Compound 20 synthesis.
  • the ketone A was converted to Compound 57 as described for Compound 56.
  • nitrile B (1 g, 3 48 mmol) was dissolved in 30 ml of ethanol and 3 ml of 10 N sodium hydroxide. To this solution was added 1 g of a 50% aqueous slurry of Raney nickel, and the mixture was hydrogenated at 60 psi for 20 hours. The reaction was filtered and concentrated to a white solid. This residue was taken up in ether/water and the ether layer separated. The ether solution was dried over sodium sulfate and concentrated to give 0.96 g of the hydroxyamine C.
  • the hydroxyamine C (0.96 g, 3 3 mmol) was taken up in concentrated HCl and heated to 70°C which caused brief solution, and then precipitation of the alkene D.
  • the alkene was collected by filtration and dissolved in 30 ml of ethanol and 1 ml of cone. HCl. Palladium dihydroxide on carbon (0.4 g) was added to the solution- and the mixture hydrogenated at 60 psi for 24 hours. The product was isolated by filtering off the catalyst and evaporating the solvent.
  • Compound 60 was accomplished as follows. Compounds 66, 69, 108, 123, 142, and 145 can be synthesized in a similar manner starting from Compounds 33, 50, 32, 60, 25 and 119, respectively.
  • Reflux was maintained for approximately 15 min, open to the air, until the reaction volume was reduced to approximately 30 ml.
  • the reaction was then cooled in an ice bath, and ice (5 g, small pieces) was carefully added followed by H 2 0 (25 ml) and cone. HCl (25 ml) .
  • the acidic solution was refluxed for 30 min.
  • the reaction mixture was then cooled in an ice bath, basified with NaOH (ION) , extracted with ether (3 X 100 ml) , dried (Na 3 SOores, anhydrous) , and evaporated under reduced pressure.
  • Compound 60 was synthesized from commercially available starting materials in the following four step reaction sequence.
  • the first intermediate in this synthetic route ethyl -N-benzyl -N-methyl - 3 - am ⁇ noprop ⁇ onate , was prepared by conjugate addition of -benzylmethylamme to ethyl acrylate.
  • the ester functionality of the first intermediate was then reacted with two equivalents of Grignard reagent (prepared from 1-bromo-3 -fluorobenzene) to provide N-benzyl -N-methyl -3-hydroxy-3-
  • reaction mixture was cooled in an ice/MeOH bath.
  • Ethyl acetate 500 mL was added to the cooled reaction mixture.
  • ⁇ aOH ION, 1.7 L was then added to the cooled mixture over a period of 25 min at such a rate as to keep the temperature below 40 °C.
  • the mixture was transferred to a 6-L separatory funnel. The organic layer was separated and the aqueous layer was extracted with ethyl acetate (2 x 500 mL) The combined organic layers were washed with satd.
  • N-Benzyl -N-methyl-3-bis (3-fluorophenyl) allylamine hydrochloride (120.0 g, 0.311 mol) was dissolved abs. EtOH (1250 mL) .
  • Pd(OH) 2 /charcoal (10.0 g, -20% Pd, Fluka Chemical) was added.
  • the reaction mixture was stirred under a steady flow of hydrogen gas for 18 h at 25 °C (atmospheric pressure) .
  • the mixture was then filtered through CeliteVfritted glass, the catalyst was washed with EtOH (2 x 50 mL) , and the solvent was removed under reduced pressure to yield 95.4 g, 103% of crude product.
  • Compound 61 was prepared from 2-bromo-4-fluoroanisole and 3-fluorobenzaldehyde as described for Compound 24.
  • m/z (relative intensity) 277 (M ⁇ 74) , 260 (46) , 245 (35) , 231 (44) , 229 (34) , 217 (24) , 203 (28) , 201 (31) , 183 (28) , 154 (24) , 133 (19) , 109 (100) .
  • the synthesis of Compound 63 was accomplished as follows .
  • Alcohol A was obtained from 3-fluorobenzaldehyde as described for product A of the Compound 24 synthesis
  • Product B (2.01 g, 9.86 mmol) was dissolved
  • the ketone A was synthesized similarly to ketone B in the Compound 24 synthesis using
  • Compound 113 was synthesized from commercially available .4,4-diphenylcyclohexenone in three steps. First, the alkene in the starting material was reduced by means of catalytic hydrogenation. Methoxylamine formation followed by reduction using standard procedures.
  • the enantiomers of Compound 136 were separated by analytical chiral HPLC. Aliquots (20 ⁇ g) were injected onto a Chiralcel-OD-R (Chiral Technologies, Inc. , Exton, PA) reversed-phase HPLC column (0.46 x 250 mm) using the following conditions: gradient elution, 40%-70% ACN (60- 30% 0.5N KTFA) over 30 mm; flow rate, 1 mL/min; detector, 264 nm. Two identically-sized peaks were collected at 21.0 and 24.4 mm. GC/MS analysis of the two samples indicate that both materials have identical GC retention times as well as identical mass spectra.
  • reaction mixture was then poured into diethyl ether (200 mL) and the resulting suspension was centrifuged to remove the titanium precipitate. The supernatant was collected and the pellet was rinsed with diethyl ether (200 mL) . The combined organic washings were evaporated under vacuum to give a crude oil which was chromatographed on silica gel (elution with 4% MeOH-CH 2 Cl 2 ) to provide 647 mg (38%) of product.

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Abstract

Procédé et compositions servant à traiter un malade atteint d'une maladie ou de troubles neurologiques, tels qu'une attaque, un traumatisme crânien, une lésion de la moelle épinière, l'ischémie de la moelle épinière, la détérioration des cellules nerveuses provoquée par l'ischémie ou par l'hypoxie, l'épilepsie, l'anxiété, des déficiences neuropsychiatriques ou cognitives dues à l'ischémie ou à l'hypoxie, telles que celles qui apparaissent fréquemment à la suite d'une chirurgie cardiaque sous circulation extra-corporelle, ou des maladies neurodégénératives, telles que la maladie d'Alzheimer, la maladie de Huntington, la maladie de Parkinson ou la sclérose latérale amyotrophique.
PCT/US1996/020697 1996-06-07 1996-12-11 Composes agissant sur un nouveau site des canaux a calcium actives par recepteur et utiles pour traiter des troubles et des maladies neurologiques WO1997046511A1 (fr)

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AU13525/97A AU723349B2 (en) 1996-06-07 1996-12-11 Coumpounds active at a novel site on receptor-operated calcium channels useful for treatment of neurological disorders and diseases
CA002257234A CA2257234C (fr) 1996-06-07 1996-12-11 Composes agissant sur un nouveau site des canaux a calcium actives par recepteur et utiles pour traiter des troubles et des maladies neurologiques
EP96945069A EP0912494A1 (fr) 1996-06-07 1996-12-11 Composes agissant sur un nouveau site des canaux a calcium actives par recepteur et utiles pour traiter des troubles et des maladies neurologiques
JP50053898A JP2002511835A (ja) 1996-06-07 1996-12-11 神経障害および神経病の治療に有用な受容体作動性カルシウムチャネル上の新規部位で活性な化合物

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WO1998056752A1 (fr) * 1997-06-11 1998-12-17 Nps Pharmaceuticals, Inc. Composes actifs sur un nouveau site des canaux calciques actives par les recepteurs servant au tratitement des troubles et des maladies neurologiques
WO2000002551A2 (fr) * 1998-07-13 2000-01-20 Nps Pharmaceuticals, Inc. Procedes et composes permettant de traiter la depression et d'autres troubles
WO2001017943A1 (fr) * 1999-09-08 2001-03-15 Targacept, Inc. Compositions pharmaceutiques et procedes d'utilisation
US6211245B1 (en) 1993-02-08 2001-04-03 Nps Pharmaceuticals, Inc. Compounds active at a novel site on receptor-operated calcium channels useful for treatment of neurological disorders and diseases
WO2001027070A1 (fr) * 1999-10-12 2001-04-19 F. Hoffmann-La Roche Ag Utilisation de derives carbonylamino contre les troubles du systeme nerveux central
US6750244B2 (en) 1993-02-08 2004-06-15 Nps Pharmaceuticals, Inc. Compounds active at a novel site on receptor-operated calcium channels useful for treatment of neurological disorders and diseases
EP1640359A2 (fr) * 1997-12-10 2006-03-29 Nps Pharmaceuticals, Inc. Bis(fluorophenyl)alkylamides ayant une activité anticonvulsivante et agissant sur le système nerveux central
US7087765B2 (en) 1995-06-07 2006-08-08 Nps Pharmaceuticals, Inc. Compounds active at a novel site on receptor-operated calcium channels useful for treatment of neurological disorders and diseases
US7446118B2 (en) 2005-11-30 2008-11-04 Roche Palo Alto Llc 3-amino-1-arylpropyl indoles and aza-substituted indoles and uses thereof
US7485732B2 (en) 2003-06-11 2009-02-03 Merck & Co., Inc. Substituted 3-alkyl and 3-alkenyl azetidine derivatives
US7598399B2 (en) 2005-11-30 2009-10-06 Roche Palo Alto Llc Methods for synthesis of 3-amino-1-arylpropyl indoles
US7638517B2 (en) 2005-11-30 2009-12-29 Roche Palo Alto Llc 3-Amino-1-arylpropyl azaindoles and uses thereof
US7863305B2 (en) 2004-06-01 2011-01-04 Roche Palo Alto Llc 3-amino-1-arylpropyl indoles as monoamine reuptake inhibitors
US7906652B2 (en) 2005-11-28 2011-03-15 Merck Sharp & Dohme Corp. Heterocycle-substituted 3-alkyl azetidine derivatives
US10188615B2 (en) 2007-10-05 2019-01-29 Acucela Inc. Alkoxy compounds for disease treatment
US10471027B2 (en) 2009-07-02 2019-11-12 Acucela, Inc. Pharmacology of visual cycle modulators
US11358971B2 (en) 2019-07-03 2022-06-14 H. Lundbeck A/S Prodrugs of modulators of the NMDA receptor
US11466027B2 (en) 2019-07-03 2022-10-11 H. Lundbeck A/S Modulators of the NMDA receptor

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DE69832302D1 (de) * 1997-12-10 2005-12-15 Nps Pharma Inc Antikonvulsive und zns-aktive bis-fluoralkylamide
WO2019076904A1 (fr) * 2017-10-16 2019-04-25 Esteve Pharmaceuticals, S.A. Dérivés de propanamine destinés au traitement de la douleur et des états pathologiques associés à la douleur

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WO1995021612A2 (fr) * 1993-02-08 1995-08-17 Nps Pharmaceuticals, Inc. Composes agissant au niveau d'un nouveau site sur des canaux calciques actives par des recepteurs, et utilises dans le traitement de troubles et de maladies neurologiques
WO1996040097A1 (fr) * 1995-06-07 1996-12-19 Nps Pharmaceuticals, Inc. Composes actifs au niveau d'un nouveau site de canaux calciques actives par recepteur, utiles dans le traitement de troubles neurologiques

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DE1793735A1 (de) * 1967-02-18 1973-07-26 Boehringer Mannheim Gmbh Tricyclisch substituierte aminoalkohole und ihre nicht toxischen salze, sowie verfahren zu deren herstellung
WO1995021612A2 (fr) * 1993-02-08 1995-08-17 Nps Pharmaceuticals, Inc. Composes agissant au niveau d'un nouveau site sur des canaux calciques actives par des recepteurs, et utilises dans le traitement de troubles et de maladies neurologiques
WO1996040097A1 (fr) * 1995-06-07 1996-12-19 Nps Pharmaceuticals, Inc. Composes actifs au niveau d'un nouveau site de canaux calciques actives par recepteur, utiles dans le traitement de troubles neurologiques

Cited By (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6211245B1 (en) 1993-02-08 2001-04-03 Nps Pharmaceuticals, Inc. Compounds active at a novel site on receptor-operated calcium channels useful for treatment of neurological disorders and diseases
US7268166B2 (en) 1993-02-08 2007-09-11 Nps Pharmaceuticals, Inc. Compounds active at a novel site on receptor-operated calcium channels useful for treatment of neurological disorders and diseases
US6750244B2 (en) 1993-02-08 2004-06-15 Nps Pharmaceuticals, Inc. Compounds active at a novel site on receptor-operated calcium channels useful for treatment of neurological disorders and diseases
US7087765B2 (en) 1995-06-07 2006-08-08 Nps Pharmaceuticals, Inc. Compounds active at a novel site on receptor-operated calcium channels useful for treatment of neurological disorders and diseases
WO1998056752A1 (fr) * 1997-06-11 1998-12-17 Nps Pharmaceuticals, Inc. Composes actifs sur un nouveau site des canaux calciques actives par les recepteurs servant au tratitement des troubles et des maladies neurologiques
EP1640359A3 (fr) * 1997-12-10 2006-04-05 Nps Pharmaceuticals, Inc. Bis(fluorophenyl)alkylamides ayant une activité anticonvulsivante et agissant sur le système nerveux central
EP1640359A2 (fr) * 1997-12-10 2006-03-29 Nps Pharmaceuticals, Inc. Bis(fluorophenyl)alkylamides ayant une activité anticonvulsivante et agissant sur le système nerveux central
WO2000002551A2 (fr) * 1998-07-13 2000-01-20 Nps Pharmaceuticals, Inc. Procedes et composes permettant de traiter la depression et d'autres troubles
WO2000002551A3 (fr) * 1998-07-13 2000-09-21 Nps Pharma Inc Procedes et composes permettant de traiter la depression et d'autres troubles
AU771252B2 (en) * 1998-07-13 2004-03-18 Nps Pharmaceuticals, Inc. Methods and compounds for treating depression and other disorders
US6337351B1 (en) 1998-10-22 2002-01-08 Targacept, Inc. Pharmaceutical compositions and methods for use
WO2001017943A1 (fr) * 1999-09-08 2001-03-15 Targacept, Inc. Compositions pharmaceutiques et procedes d'utilisation
US6548522B1 (en) 1999-10-12 2003-04-15 Hoffmann-La Roche Inc. Method for treating conditions related to the glutamate receptor using carboxylic acid amide derivatives
WO2001027070A1 (fr) * 1999-10-12 2001-04-19 F. Hoffmann-La Roche Ag Utilisation de derives carbonylamino contre les troubles du systeme nerveux central
AU775656B2 (en) * 1999-10-12 2004-08-12 F. Hoffmann-La Roche Ag Use of carbonylamino derivatives against CNS disorders
US7485732B2 (en) 2003-06-11 2009-02-03 Merck & Co., Inc. Substituted 3-alkyl and 3-alkenyl azetidine derivatives
US7906503B2 (en) 2003-06-11 2011-03-15 Merck Sharp & Dohme Corp. Substituted 3-alkyl and 3-alkenyl azetidine derivatives
US7863305B2 (en) 2004-06-01 2011-01-04 Roche Palo Alto Llc 3-amino-1-arylpropyl indoles as monoamine reuptake inhibitors
US7906652B2 (en) 2005-11-28 2011-03-15 Merck Sharp & Dohme Corp. Heterocycle-substituted 3-alkyl azetidine derivatives
US7598399B2 (en) 2005-11-30 2009-10-06 Roche Palo Alto Llc Methods for synthesis of 3-amino-1-arylpropyl indoles
US7803830B2 (en) 2005-11-30 2010-09-28 Roche Palo Alto Llc 3-amino-1-arylpropyl indoles and AZA-substituted indoles and uses thereof
US7638517B2 (en) 2005-11-30 2009-12-29 Roche Palo Alto Llc 3-Amino-1-arylpropyl azaindoles and uses thereof
US7446118B2 (en) 2005-11-30 2008-11-04 Roche Palo Alto Llc 3-amino-1-arylpropyl indoles and aza-substituted indoles and uses thereof
US10188615B2 (en) 2007-10-05 2019-01-29 Acucela Inc. Alkoxy compounds for disease treatment
US10639286B2 (en) 2007-10-05 2020-05-05 Acucela Inc. Alkoxy compounds for disease treatment
US11446261B2 (en) 2007-10-05 2022-09-20 Acucela Inc. Alkoxy compounds for disease treatment
US12029708B2 (en) 2007-10-05 2024-07-09 Acucela Inc. Alkoxy compounds for disease treatment
US10471027B2 (en) 2009-07-02 2019-11-12 Acucela, Inc. Pharmacology of visual cycle modulators
US11358971B2 (en) 2019-07-03 2022-06-14 H. Lundbeck A/S Prodrugs of modulators of the NMDA receptor
US11466027B2 (en) 2019-07-03 2022-10-11 H. Lundbeck A/S Modulators of the NMDA receptor

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