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WO1997004797A1 - Utilisation d'inhibiteurs calciques des neurones pour fabriquer un medicament destine au traitement des psychoses, de la schizophrenie ou de la dependance vis-a-vis des amphetamines ou de la cocaine - Google Patents

Utilisation d'inhibiteurs calciques des neurones pour fabriquer un medicament destine au traitement des psychoses, de la schizophrenie ou de la dependance vis-a-vis des amphetamines ou de la cocaine Download PDF

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Publication number
WO1997004797A1
WO1997004797A1 PCT/US1996/011365 US9611365W WO9704797A1 WO 1997004797 A1 WO1997004797 A1 WO 1997004797A1 US 9611365 W US9611365 W US 9611365W WO 9704797 A1 WO9704797 A1 WO 9704797A1
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WO
WIPO (PCT)
Prior art keywords
conotoxin
compound
cocaine
treatment
amphetamine
Prior art date
Application number
PCT/US1996/011365
Other languages
English (en)
Inventor
Thomas Gary Heffner
Michael Francis Rafferty
James Nicholson Wiley
Original Assignee
Warner-Lambert Company
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Warner-Lambert Company filed Critical Warner-Lambert Company
Priority to AU64540/96A priority Critical patent/AU6454096A/en
Publication of WO1997004797A1 publication Critical patent/WO1997004797A1/fr

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Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/1703—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates

Definitions

  • VACC voltage-activated calcium channels
  • a family of peptides have been isolated from the venom of fish-eating marine snails of the genus Conus which potently and specifically antagonize the so-called N-type VACC.
  • these toxins When applied to CNS neuronal preparations, these toxins have been found to inhibit the evoked release of catecholamines such as norepinephrine and dopamine (Olivera, et al. , Annual Review of Biochemistry, 1994;63:823-867).
  • catecholamines such as norepinephrine and dopamine
  • amphetamine and cocaine which have been reported to produce psychotic states in man, have also been found to enhance dopamine neurotransmission within the CNS (Evenden J.L. and Ryan C.N., in "Psychotropic Drugs of Abuse," Balfour D.J.K., ed. , Pergamon Press, 1990:1-21).
  • administration of amphetamine and cocaine has been demonstrated to induce well-characterized behaviors which can be prevented or reversed by the administration of neuroleptics .
  • amphetamine and cocaine are potent stimulants in rodents, resulting in a well-characterized increase in spontaneous locomotor activity (Kline E.J., et al. , Journal of Pharmacology and Experimental Therapeutics, 1992;260:1174-1179).
  • Amphetamine-induced behaviors have therefore become a commonly used preclinical screen for drugs to treat schizophrenia and related psychoses.
  • Cocaine is a potent and specific blocker of the reuptake of dopamine by neurons .
  • Dopamine reuptake is an important mechanism for the termination of dopamine- dependent synaptic neurotransmission. Therefore, the psychotomimetic and CNS stimulant effects of cocaine also appear to be a manifestation of increased dopamine neurotransmission (Evenden J.L. and Ryan C.N., ibid. ) .
  • the instant invention is the administration of a specific Conus venom constituent which blocks N-type VACCs and can suppress the behavioral actions of amphetamine or cocaine at doses which when administered alone do not alter normal behavior in animals .
  • the instant invention is to the use of compounds which block calcium influx through neuronal voltage- activated calcium channels to treat schizophrenia and related psychiatric diseases, to treat psychotic episodes induced by cocaine or other related drugs of abuse, and to treat acute psychotic episodes resulting from amphetamine toxicity.
  • the preferred compounds useful in the exercise of the instant invention are ⁇ -conotoxin MVlla, ⁇ -conotoxin GVla, and ⁇ -conotoxin TVla (SNX-185) (Fox J.A. , Heuroflclence Letters , 1994;165:157-160).
  • the compounds may be useful as an acute therapy for psychotic episodes by parenteral administration.
  • the preferred compounds are the first with this mechanism found suitable for the treatment of psychosis and the emergency treatment of cocaine- or amphetamine- induced psychotic episodes by parenteral injection.
  • Figure 1 illustrates the time in minutes of the effect of SNX-185 on spontaneous locomotor activity in mice.
  • Figure 2 illustrates the effect of amphetamine treatment on the level of spontaneous locomotor activity in mice, and the ability of the antipsychotic agent haloperidol to block the actions of amphetamine in mice.
  • Figure 3 illustrates the effect of SNX-185 at various doses on the behavioral effects of amphetamine in mice.
  • Figure 4 illustrates the effect of SNX-185 on the stimulant properties of cocaine in mice.
  • the compounds of the invention were tested for their ability to inhibit locomotor activity in mice either as a measure of normal behaviors or following administration of a CNS stimulant as a measure of antipsychotic activity according to the assay described in McLean J.R., et al. , Pharmacology, Biochemistry, and Behavior, 1978;8:97-99.
  • CNS stimulants employed in the characterization of the compounds identified in this invention include amphetamine and cocaine.
  • the ability of compounds of the invention to block apomorphine- induced climbing was evaluated using the method of Constentin J., et al. , Psychopharmacology, 1976;50:1-6.
  • the ability of the compounds to attenuate mescaline- induced scratching was evaluated using the method of Fellows E.J. and Cook L., in "Psychotropic Drugs," Garrattivi S. and Ghatti V. , eds., Elsevier (Amsterdam), 1957:397-404.
  • Phencyclidine (PCP) -induced ataxia was measured and apomorphine using the following procedure.
  • Male Swiss-Webster mice weighting 20 to 30 g were treated with test compounds, followed after 10 minutes by an intraperitoneal injection of PCP (4 mg/kg) . Fifteen minutes later, animals were placed on an inverted screen and evaluated for their ability to remain on the screen. At this dose of PCP, typically 60% to 100% of the animals fail this test. A dose-response determination is carried out for those compounds which display an ability at an initial test dose to attenuate the ataxic effects of PCP.
  • Table 1 summarizes the data for these and other experiments .
  • a lack of effect on the behavioral properties of phencyclidine or mescaline is evidence for pharmacological specificity by ⁇ -conotoxin TVla toward dopamine-dependent behaviors.
  • the lack of effect on apomorphine-induced behaviors is evidence for an effect of ⁇ -conotoxin TVla on dopamine release, rather than on the actions of dopamine at postsynaptic receptors.
  • the lack of effect by ⁇ -conotoxin TVla in this last experiment clearly distinguishes it from haloperidol, which potently blocks the effects of apomorphine.
  • haloperidol and other neuroleptics evidence that this mechanism will confer therapeutic advantages over haloperidol and other neuroleptics is found in the fact that ⁇ -conotoxin TVla can suppress dopamine-dependent evoked behaviors at doses which alone do not alter normal behavior. In contrast, the doses of haloperidol required to suppress amphetamine-induced stimulation also suppress basal behavior.
  • Figure 2 shows the inhibitory effect of haloperidol, which is a potent dopamine receptor blocker and widely used antipsychotic agent on the stimulant property of amphetamine in the locomotor activity chamber. The ED ⁇ Q dose of haloperidol given intraperitoneally was calculated to be 0.02 mg/kg.
  • Figure 3 shows the ability of ⁇ -conotoxin TVla to reverse amphetamine-induced stimulation in this same paradigm.
  • the ED ⁇ Q value in this experiment was 8.9 ng, which is well below the dose required to alter normal behavioral activity.
  • This experiment demonstrated a common behavioral profile for ⁇ -conotoxin TVla with a known antipsychotic drug in a model which has been used for purposes of predicting clinically useful antipsychotic activity.
  • Figure 4 shows the ability of ⁇ -conotoxin TVla to reverse the stimulant effects of cocaine in mice.
  • the ED 50 value for ⁇ -conotoxin TVla administered intraventricularly in this experiment was calculated to be approximately 10 ng.
  • the compounds of the present invention can be prepared and administered in a wide variety of parenteral dosage forms.
  • the compounds of the present invention can be administered by injection, that is, intravenously, intramuscularly, intracutaneously, subcutaneously, intraduodenally, or intraperitoneally.
  • the compounds of the present invention can be administered by inhalation, for example, intranasally.
  • the compounds of the present invention can be administered transdermally. It will be obvious to those skilled in the art that the following dosage forms may comprise as the active component, either a compound of Formula I or a corresponding pharmaceutically acceptable salt of a compound of Formula I .
  • pharmaceutically acceptable carriers can be either solid or liquid.
  • Solid form preparations include powders and dispersible granules.
  • a solid carrier can be one or more substances which may also act as diluents, flavoring agents, solubilizers, lubricants, suspending agents, binders, preservatives, tablet disintegrating agents, or an encapsulating material.
  • the carrier is a finely divided solid which is in a mixture with the finely divided active component.
  • the powders preferably contain from five or ten percent to about seventy percent of the active compound.
  • Suitable carriers are magnesium carbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin, starch, gelatin, tragacanth, methylcellulose, sodium carboxymethylcellulose, a low melting wax, cocoa butter, and the like.
  • the term "preparation" is intended to include the formulation of the active compound with appropriate material as a carrier.
  • Liquid form preparations include solutions, suspensions, and emulsions, for example, water or water propylene glycol solutions. For parenteral injection, liquid preparations can be formulated in solution in aqueous polyethylene glycol solution.
  • the pharmaceutical preparation is preferably in unit dosage form.
  • the preparation is subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation.
  • the quantity of active component in a unit dose preparation may be varied or adjusted from 1 mg to 1000 mg, preferably 10 mg to 100 mg according to the particular application and the potency of the active component.
  • the composition can, if desired, also contain other compatible therapeutic agents.
  • the compounds utilized in the pharmaceutical method of this invention are administered at the initial dosage of about 1 mg to about 50 mg per kilogram daily.
  • a daily dose range of about 5 mg to about 25 mg per kilogram is preferred.
  • the dosages may be varied depending upon the requirements of the patient, the severity of the condition being treated, and the compound being employed. Determination of the proper dosage for a particular situation is within the skill of the art. Generally, treatment is initiated with smaller dosages which are less than the optimum dose of the compound. Thereafter, the dosage is increased by small increments until the optimum effect under the circumstance is reached. For convenience, the total daily dosage may be divided and administered in portions during the day if desired.
  • the compounds of the invention are preferably formulated for parenteral administration, for example, in emergency situations in a suitable inert carrier such as a sterile physiological saline solution.
  • a suitable inert carrier such as a sterile physiological saline solution.
  • concentration of the compound in the carrier is about 0.1-10 mg/mL.
  • the dose administered will be determined by the route of administration and as determined by a skilled physician.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Immunology (AREA)
  • Medicinal Chemistry (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Marine Sciences & Fisheries (AREA)
  • Zoology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Epidemiology (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Inhibiteurs calciques des neurones de type φ-conotoxine MVlla, φ-conotoxine GVla et φ-conotoxine TVla utiles dans le traitement de crises psychotiques résultant de troubles psychiatriques ou de la toxicité provoquée par de la cocaïne ou des amphétamines.
PCT/US1996/011365 1995-07-26 1996-07-08 Utilisation d'inhibiteurs calciques des neurones pour fabriquer un medicament destine au traitement des psychoses, de la schizophrenie ou de la dependance vis-a-vis des amphetamines ou de la cocaine WO1997004797A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU64540/96A AU6454096A (en) 1995-07-26 1996-07-08 Use of neuronal calcium channel blockers for the manufacture of a medicament for the treatment of psychoses, schizophrenia and cocaine or amphetamine addiction

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US151895P 1995-07-26 1995-07-26
US60/001,518 1995-07-26

Publications (1)

Publication Number Publication Date
WO1997004797A1 true WO1997004797A1 (fr) 1997-02-13

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PCT/US1996/011365 WO1997004797A1 (fr) 1995-07-26 1996-07-08 Utilisation d'inhibiteurs calciques des neurones pour fabriquer un medicament destine au traitement des psychoses, de la schizophrenie ou de la dependance vis-a-vis des amphetamines ou de la cocaine

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AU (1) AU6454096A (fr)
WO (1) WO1997004797A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20020022748A (ko) * 2002-03-07 2002-03-27 동성 김 투명성을 가지는 판상형태의 고흡수성 수지의 제조방법

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5364842A (en) * 1991-12-30 1994-11-15 Neurex Corporation Method of producing analgesia
EP0656362A1 (fr) * 1993-12-03 1995-06-07 Lilly Industries Limited Composés chimiques

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5364842A (en) * 1991-12-30 1994-11-15 Neurex Corporation Method of producing analgesia
EP0656362A1 (fr) * 1993-12-03 1995-06-07 Lilly Industries Limited Composés chimiques

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
KIYOFUMI YAMADA ET AL.: "w-Conotoxin GVIA inhibits the methylphenidate-induced but not methamhetamine-induced behavior", NEUROSCIENCE LETTERS, vol. 165, 1994, pages 191 - 194, XP000603050 *
MARTIN D. SCHECHTER: "Cocaine discrimination is attenuated by Isaradipine and CGS 10746B", PHARMACOL. BIOCHEM. BEHAV., vol. 44, no. 3, 1993, pages 661 - 664, XP000603072 *
NICHOLAS A. MOORE ET AL.: "Effect of L-type calcium channel modulators on stimulant-induced hyperactivity", NEUROPHARMACOLOGY, vol. 32, no. 7, 1993, pages 719 - 720, XP000603063 *
RICHARD B. ROSSE ET AL.: "Nimodipine pharmacotherapeutic adjuvant therapy for inpatient treatment of cocaine dependence", CLIN. NEUROPHARMACOL., vol. 17, no. 4, 1994, pages 348 - 358, XP000603059 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR20020022748A (ko) * 2002-03-07 2002-03-27 동성 김 투명성을 가지는 판상형태의 고흡수성 수지의 제조방법

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