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WO1998037097A1 - Peptides cycliques selectifs vis-a-vis de sous-types de recepteurs msh - Google Patents

Peptides cycliques selectifs vis-a-vis de sous-types de recepteurs msh Download PDF

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Publication number
WO1998037097A1
WO1998037097A1 PCT/SE1998/000270 SE9800270W WO9837097A1 WO 1998037097 A1 WO1998037097 A1 WO 1998037097A1 SE 9800270 W SE9800270 W SE 9800270W WO 9837097 A1 WO9837097 A1 WO 9837097A1
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WIPO (PCT)
Prior art keywords
cys
arg
trp
gly
glu
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PCT/SE1998/000270
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English (en)
Inventor
Jarl Wikberg
Ruta Muceniece
Felikss Mutulis
Peteris Prusis
Helgi-Birgir SCHIÖTH
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Wapharm Ab
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Priority to AU61274/98A priority Critical patent/AU6127498A/en
Priority to EP98905907A priority patent/EP1025127A1/fr
Publication of WO1998037097A1 publication Critical patent/WO1998037097A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/665—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin
    • C07K14/68—Melanocyte-stimulating hormone [MSH]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to new MSH-receptor subtype selective cyclic peptide compounds having unique binding properties to the melanocortin (MC) receptors (MSH-receptors), and to their use in the treatment of conditions affected by those receptors in anmals including man.
  • MC melanocortin
  • Melanocortic peptides are natural peptide hormones in animals and man binding to and stimulating MC-receptors.
  • melanocortins are ⁇ -MSH, ⁇ -MSH, ⁇ -MSH, ACTH and their peptide fragments.
  • ⁇ -MSH is mainly known for its ability to regulate peripheral pigmentation (Eberle 1988)
  • ACTH is known to induce steroidoneogenesis (Simpson and Waterman, 1988).
  • the melanocortic peptides also mediate a number of other physiological effects.
  • MC-receptors By use of molecular cloning genes encoding five different subtypes of MC-receptors were identified (Chhajlani et al., 1993; Chhajlani and Wikberg, 1992; Gantz et al., 1993a & b; Mountjoy et al., 1992).
  • the MC-receptors belong to the class of G-protein coupled receptors which are all built from a single peptide forming 7 transmembrane domains.
  • the five MC-receptors are termed MC1 , MC2, MC3, MC4 and MC5 and they all couple in a stimulatory fashion to cAMP. Of these the MC2-receptor is the ACTH-receptor whereas the others constitute subtypes of MSH-receptors.
  • the MC1 -receptor is present on melanocytes and melanoma cells (Low et al., 1994, Siegrist & Eberle, 1995). Recent data also indicate that the MC1 -receptor is expressed in limited areas (periaqueductal gray) of the rat and human brains (Xia et al. 1995), as well as in the testis (Vanetti et al. 1994).
  • the MC2-receptor is the ACTH receptor and is present in the cortex of the adrenal gland.
  • the MC3-receptor mRNA has been found in distinct areas of the brain, as well as in placental and gut tissues (Gantz et al. 1993a, Desarnaud et al.
  • the MC4-receptor has been found in the brain only (Gantz et al. 1993b; Mountjoy et al 1994).
  • the MC5-receptor is expressed in the brain, as well as in several peripheral tissues (Chhajlani et al 1993; Gantz et al 1994; Griffon et al 1994; Labb ⁇ et al. 1994; Barrett et al. 1994; Fathi et al. 1995). More recent data indicate that all the 5 cloned MC-receptors have a wider tissue distribution (Chhajlani, 1996) than originally thought.
  • the five MC-receptors show unique affinities for the melanocortic peptides (Schi ⁇ th et al., 1995, Schi ⁇ th et al., 1996a,b,c).
  • the MC1 -receptor shows high affinity for ⁇ -MSH, but lower affinities for ⁇ -MSH, ⁇ -MSH, and ACTH.
  • MC2-receptor (the ACTH receptor) binds ACTH with high affinity, but does not bind the MSH peptides.
  • the MC3-receptor shows slightly higher affinity for ⁇ -MSH compared to ⁇ and ⁇ -MSH.
  • the MC4-receptor shows slight preference for ⁇ -MSH over ⁇ -MSH, and a very low affinity for ⁇ -MSH.
  • the MC5- receptor shows the same potency order for the MSH peptides as the MC1 -receptor, although it binds the peptides with much lower affinities. The overall picture is that these peptides are all selective for the MC1 -receptor (Schi ⁇ th et al., 1995, Schi ⁇ th et al., 1996a,b,c).
  • Natural melanocortic peptides show various effects not yet related to the different MC-receptor subtypes. It is believed that these effects are mediated by different MC-receptors and that many of them are mediated by the newly discovered MC3, MC4 and MC5 receptors. MC-receptor subtypes have, for instance, been attributed to the control of eating and body weight in agouti (Fan et al. 1997). The wide distribution of MC4 receptors in the central nervous system also prompts them as a target for neuroprotective treatment.
  • MSH-receptors have been known as physiological entities since 1957. Binding sites for MSH/ACTH peptides have been identified in various brain and peripheral tissues (Hnatowich et al., 1989, Tatro & Reichlin, 1987, Lichtensteiger et al., 1993, Tatro & Entwistle, 1994). Peptide structure activity studies for these receptors have been performed on melanophores from lower vertebrates like Rana pipiens (frog), Anolis carolinensis (lizard) and Xenopus laevis. Receptor studies were later also performed by binding to melanoma cell lines. These test systems gave comparable results.
  • cyclic MC-receptor activating and/or blocking peptides of the general formula (1 ):
  • LRG is large aminoacid and L is linker connecting LRG and Trp, thereby forming a cycle having from 26 to 29, preferably 29 members.
  • 26 to 29 members in this context is meant that the ring contains from 26 to 29 atoms.
  • 'MC-receptor activating and/or blocking' denotes the capacity of a compound of the invention to activate and/or block certain MC receptor(s).
  • a preferred aspect of the invention are cyclic MC-receptor activating and/or blocking peptides of the formula (1 ) wherein L is:
  • X is a non-cyclic peptide of two to three aminoacids
  • Y is a non-cyclic peptide of one to two aminoacids
  • a and B are non-cyclic peptides, each of from 0 to 5 aminoacids, and in which the cystein residues are connected by a disulphide bond.
  • formula (2) it is understood that neither of A, X, Y and B are connected to each other with covalent bond(s).
  • aminoacid refers to alanine, arginine, asparagine, aspartic acid, p-benzoyl-phenylalanine, ⁇ -cyclohexyl-alanine, cysteine, glutamic acid, glutamine, glycine, histidine, iso- leucine, leucine, lysine, methionine, ⁇ -(2-naphtyl)-alanine, norleucine, phenyl- alanine, proline, serine, threonine, tryptophan, tyrosine, valine, 3,4-dichlorophenylalanine, 4-fluorophenylalanine, 4-nitrophenylalanine, 2-thienylalanine, 3-benzothienylalanine, 4-cyanophenylalanine, 4-iodophenylalanine, 4-bromophenylalanine, 4,4'
  • R is H or CH 2 R 1 , wherein R 1 is H, alkyl, substituted alkyl, heteroalkyl, substituted heteroalkyl, alkenyl, substituted alkenyl, heteroalkenyl, substituted heteroalkenyl, alkynyl, substituted alkynyl, heteroalkynyl, substituted hetero- alkynyl, cycloalkyl, substituted cycloalkyl, cycloheteroalkyl, substituted cycloheteroalkyl, cycloalkenyl, substituted cycloalkenyl, cycloheteroalkenyl, substituted cycloheteroalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, or functional group
  • NT is selected from H, functional group and bond to another aminoacid
  • CT is selected from functional group or bond to another aminoacid, the compounds according to formula (3) being in either D- or L-conformation.
  • large aminoacid refers to aminoacids in which R of formula (3) contains at least 14 atoms, preferably at least 15 atoms, with the D-form also being preferred and with phenylalanine being excluded. Most preferred are large aminoacids selected from the group of D- ⁇ -(2-naphtyl)-alanine, D-p-benzoyl-phenylalanine, D- ⁇ -cyclohexylalanine, D-3,4-dichlorophenylalanine, D-4-fluorophenylalanine, D-4-nitrophenylalanine, D-2-thienylalanine, D-3-benzothienylalanine,
  • alkyl as employed herein by itself or as part of another group includes a straight or branched hydrocarbon chain of up to 18, preferably from 1 to 8 carbon atoms, such as methyl, ethyl, propyl, isopropyl, tert-butyl, butyl, pentyl, hexyl, heptyl and octyl.
  • heteroalkyl as employed herein by itself or as part of another group refers to alkyl in which one or several carbon atoms are exchanged for heteroatom.
  • alkenyl as employed herein by itself or as part of another group includes a straight or branched hydrocarbon chain of up to 18 carbon atoms, preferably from 2 to 8 carbon atoms, comprising one or several carbon-carbon double bonds, such as propenyl, butenyl, pentenyl.
  • heteroalkenyl as employed herein by itself or as part of another group refers to alkenyl where one or several carbon atoms are exchanged for heteroatom.
  • alkynyl as employed herin by itself or as part of another group refers to alkyl or alkenyl containing one or several carbon-carbon triple bonds.
  • heteroalkynyl refers to heteroalkyl or heteroalkenyl containing one or several carbon-carbon triple bonds.
  • cycloalkyl as employed herein by itself or as part of another group refers to cyclic hydrocarbons containing from 3 to 12 carbons, preferably 3 to 8 carbons, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, which may optionally be fused with 1 or 2 cycles, each cycle being independently selected from the group consisting of cycloalkyl, cycloheteroalkyl, cycloalkenyl, cycloheteroalkenyl, aryl and/or heteroaryl.
  • cycloheteroalkyl as employed herein by itself or as part of another group refers to cycloalkyl in which one or several carbon atoms are exchanged for heteroatom.
  • cycloalkenyl as employed herein by itself or as part of another group refers to cycloalkyl containing one or several carbon-carbon double bods, such as cyclopentenyl and cyclohexenyl.
  • cycloheteroalkenyl as employed herein by itself or as part of another group refers to cycloheteroalkyl where one or more bonds between carbons, carbon and heteroatom, or heteroatoms are double.
  • aryl as employed herein by itself or as part of another group refers to phenyl which may optionally be fused with 1 or 2 cycles which are independently selected from the group consisting of cycloalkyl, cycloheteroalkyl, cykloalkenyl, cycloheteroalkenyl, aryl, and/or heteroaryl.
  • heteroaryl refers to a 5- to 12-membered aromatic ring, preferably a 5- to 6-membered aromatic ring, which includes one or more heteroatoms, and which may optionally be fused with 1 or 2 cycles which are independently selected from the group consisting of cycloalkyl, cycloheteroalkyl, cykloalkenyl, cyclohetero- alkenyl, aryl, and/or heteroaryl.
  • substituted refers to one or several hydrogens being substituted, independently, by alkyl, fluorinated alkyl, alkenyl, fluorinated alkenyl, alkynyl, fluorinated alkynyl, cycloalkyl, fluorinated cycloalkyl, cycloheteroalkyl, fluorinated cycloheteroalkyl, cycloalkenyl, fluorinated cycloalkenyl, cyclo- heteroalkenyl, fluorinated cycloheteroalkenyl, aryl, fluorinated aryl, heteroaryl, fluorinated heteroaryl and/or functional group.
  • a "substituted" structure is a cyclic structure fused with other cyclic structure(s) these latter cyclic structure(s) may also be substituted.
  • halogen as employed herein by itself or a part of another group refers to chlorine, bromine, fluorine and iodine with chlorine being preferred.
  • heteroatom refers to nitrogen, oxygen or sulphur, to which one or more hydrogens may be connected according to heteroatom valence; in the case of nitrogen one oxygen atom may be optionally connected to it by donor or acceptor bond, such as forming an N -oxide.
  • the term "functional group" as employed herein by itself or as part of another group refers to amino, alkylamino, dialkylamino, arylamino, arylazido, hetero- arylamino, heteroarylazido, hydroxy, alkylhydroxy, fluorinated alkylhydroxy, cyano, carboxy, alkylcarboxy, arylcarboxy, guanidino, halogen, nitro, hydroxyl- amino, acyl, fluorinated acyl, nitroso, sulfonyl, sulfinyl, thio, alkylthio, or arylthio.
  • fused as employed herein by itself or as part of another group refers to two or three cycles having one or more common atoms, the preferred maximum number of fused cycles being three.
  • Glu Glutamic acid
  • Asn Asparagine
  • Gin Glutamine
  • Nle Norleucine
  • Bpa p-Benzoyl-phenylalanine
  • Nal ⁇ -2-Naphtyl-alanine
  • the compounds of the present invention bind preferentially to particular MC-receptor subtypes. This binding capacity becomes evident when tested on recombinant human MC-receptors by use of methods described in the literature (see Schi ⁇ th et al., Eur. J. Pharmacol., Mol. Pharm. Sect. 1995, 288, 311 and Pharmacol. & Toxicol. 1996, 79, 161 ). In these tests the ability of the compounds to compete for the binding of [ 125 l]-labelled NDP-MSH ([Nle 4 , D-Phe ] ⁇ -MSH) to recombinant human MC-receptor subtypes expressed in COS-1 cells were evaluated, as described in Example 10. By these assays the dissociation constants (KJS) were determined for a number of the compounds according to the invention (Table 1 ).
  • the Kj-values for non-labeled NDP-MSH and the natural MSH-peptides are given for comparison, the affinity profile for these peptides being MC1 >MC3>MC4>MC5, which is a pattern close to that found for most previously known MC-receptor active compounds (Schi ⁇ th et al. 1995, 1996b).
  • the compounds of the invention show an affinity profile substantially different from that of known MC-receptor activating and/or blocking peptides, with selectivities balanced between MC1 , MC3, MC4 and MC5-receptors, the affinity profile for individual compounds according to the invention being balanced towards one, two or a few of the MC-receptor subtypes.
  • the compounds also show remarkably high affinities for specific subtypes of the MC-receptors.
  • the present invention comprises the combination of the optimal ring size of the cyclic peptide, being 26 to 29 membered, with the inclusion of large aminoacid (LRG) according to formula (1 ), which in general give a compound with unique and novel properties.
  • LRG large aminoacid
  • the unique and novel properties consist, on one hand, of a preferential (selective) ability of a compound of the invention to bind to one or several of the MC3, MC4 and MC5 receptors compared to its ability to bind to the MC1 receptor.
  • novel property consist, on the other hand, in addition on a very high affinity of many of the compounds of the invention for one or several of the MC3, MC4 and MC5 receptors, concomitantly with its preferential (selective) binding ability mentioned in the aforementioned sentence.
  • the MC3-selectivity of a compound is defined as the ratio of the Kj of the compound for an MC1 receptor ( -MC1 ) over the Kj of the compound for the MC3 receptor ( -MC3), the K* values being measured as described in Example 10 using the method described by Schi ⁇ th et al. 1995 and 1996b, hence:
  • the MC4-selectivity of a compound as the ratio of the Kj of the compound for an MC1 receptor (Kj -MC1 ) over the K, of the compound for the MC4 receptor ( -MC4), the Kj values being measured as described in Example 10 using the method described by Schi ⁇ th et al. 1995 and 1996b, hence:
  • the MC5-selectivity of a compound as the ratio of the of the compound for an MC1 receptor ( -MC1 ) over the Kj of the compound for the MC5 receptor ( -MC5), the values being measured as described in Example 10 using the method described by Schi ⁇ th et al. 1995 and 1996b, hence:
  • a compound is herein defined as being selective for the MC3 receptor when the above mentioned ratio "MC3-selectivity" is preferably at least 3, somewhat more preferably at least 5, more preferably at least 10, even more preferably at least 20 and most preferably at least 30.
  • a compound is herein defined as being selective for the MC4 receptor when the above mentioned ratio "MC4-selectivity" is preferably at least 3, somewhat more preferably at least 5, more preferably at least 10, even more preferably at least 20 and most preferably at least 30.
  • a compound is herein defined as being selective for the MC5 receptor when the above mentioned ratio "MC5-selectivity" is preferably at least 3, somewhat more preferably at least 5, more preferably at least 10, even more preferably at least 20 and most preferably at least 30.
  • a "very high affinity" of a compound of the invention for an MC3 or MC4 or MC5 receptor is in the present patent meant a value for the respective receptor being preferably less than 300 nM, somewhat more preferably being less than 100 nM, more preferably being less than 30 nM, even more preferably being less than 10 nM and most preferably being less than 3 nM; the Kj value being measured as described in Example 10 using the method described by Schi ⁇ th et al. 1995 and 1996b.
  • the MC3-selectivity and/or MC4-selectivity and/or MC5-selectivity, including the optional very high affinity of a compound of the invention for the MC3 and/or MC4 and/or MC5 receptor is a very desired property as this avoids side effects of the compound of the invention by not causing actions on the MC1 receptor (e.g. effects on skin pigmentation).
  • the compounds of the invention can be used for the treatment and diagnosis of diseases, disorders and/or pathological conditions in an animal, in particular in a mammal, but they are most preferably used for these purposes in man.
  • the compound of the invention is administered in form of a pharmaceutical composition
  • a pharmaceutical acceptable carrier and, optionally, tabletting agents, wetting agents, binders and fillers, preservatives, such as antioxidants and anti-microbial agents, buffers and salts.
  • Preferred carriers comprise injection media, particularly water and other conventional media for injection.
  • the compositions are administered by any conventional route including the oral, enteral, rectal and parenteral routes. Parenteral routes comprise intravenous, intramuscular, subcutaneous and peritoneal injection.
  • the compounds of the invention may also be administered by inhalation, as nasal spray, and topically on the skin. They may also be administered epidurally, intrathecally and intracerebro-ventricularly.
  • the pharmaceutical composition containing a pharmacologically effective amount of a compound of the invention is administered to an animal, in particular man, for diagnosis, prevention or therapeutic treatment of diseases, in particular conditions involving MC3- and/or MC4- and/or MC5-receptors.
  • diseases in particular conditions involving MC3- and/or MC4- and/or MC5-receptors.
  • MC3- and/or MC4- and/or MC5-receptor related conditions that are positively affected by administration of the compounds of the invention are fever, pain, chronic inflammatory diseases, memory disturbances in particular in elderly people, including Alzheimer's disease.
  • positive effects are obtained on the regeneration of nerves after nerve injuries, on psychomotor functions, in particular positive effects on pathological psychomotor functions of psychiatric conditions such as e.g. catatonic conditions.
  • the compounds of the invention are also be used for mediating anti-epileptic, anti-inflammatory and anti-pyretic effects, and for modulating signaling functions in both the brain and the periphery.
  • Another important use of the compounds of the invention constitutes the treatment of weight disorders (e.g. overweight and underweight), in particular when the weight disorder is related to an eating disorder, such as excessive food intake, reduced food intake, bulimia and/or anorexia, with respect to the latter in particular anorexia nervosa, of humans.
  • weight disorders e.g. overweight and underweight
  • an eating disorder such as excessive food intake, reduced food intake, bulimia and/or anorexia, with respect to the latter in particular anorexia nervosa
  • Particularly useful for treatment of such disorders are compounds HS007, HS011 , MS012, HS014, HS024, HS028 and HS964 due to the fact that they are balanced in their selectivities towards the MC4-receptor.
  • a particularly important aspect of the invention is the use of the compounds of the invention for treatment of eating disorders related to underweight, cachexia or anorexia of any cause in humans.
  • the administration of a compound of the invention will increase food intake, which improves the patients general condition, increases or restores their body weight and prolong their life.
  • the administration of the compound of the invention is beneficial in elderly patients, in cancer patients, and in patients treated with cancer chemotherapeutics, as these patients often suffers from lack of appetite, that often lead to decreased food intake and severe underweight.
  • Yet another important embodiment of the invention is the administration of the compound of the invention to an animal to increase its rate of growth. In particular the latter is desired in animal breeding for meat production.
  • Very particular embodiments of the present invention constituting the administration of HS014 and HS028 for increasing food intake, for increasing body weight and for increasing rate of growth are given in Examples 57 and 58.
  • compounds of the invention are for treatment of disturbances in: 1 ) placental development, 2) aldosterone synthesis and release, 3) thyroxin release, 4) spermatogenesis, 5) prolactin and FSH secretion, 6) sebum and/or pheromone secretion, 7) blood glucose levels, 8) natriuresis, and 9) intrauterine foetal growth.
  • compounds of the invention may be used for the treatment of uterine bleeding in women.
  • Other important uses constitute control of blood pressure, heart rate, vascular tone and brain blood flow, and to afford neuroprotection.
  • Pharmacologically effective amounts may vary from 0.001 mg/day/kg body weight to 1 ,000 mg/day/kg body weight; however, lower amounts may be effective, in particular if delivered locally.
  • the compounds of the invention have low toxicity and are well tolerated.
  • the compounds of the present invention can be used in radioactive form, including radioactive labels.
  • the compounds of the invention may be manufactured so as to incorporate radioactive iodine or tritium, or any other suitable radio nuclide.
  • a radioactively labeled compound can be used in radioligand binding for the the quantification of specific melanocortin receptors, for the analysis of dissociation constant (KjS or K d S) of drugs competing with specific subtypes of melanocortin receptors, and for the localization of MC-receptors in tissues and tissue sections e.g. by use of receptor autoradiographic techniques. Principles of radioligand binding and receptor autoradiography are well known in the art.
  • the compound may be labeled with any other type of label that allows detection of the substance, e.g. a fluorescent label or biotin, and the resulting compound be used for the similar purpose as the radioactively labeled compound.
  • the compounds of the invention can also be manufactured so as to incorporate a group that can be activated by light, in particular UV-light, the purpose with such activation being to obtain a compound useful for covalent labeling of MC-receptor by use of the photoaffinity labeling technique.
  • Photoaffinity labeling is a technique well known in the art which in the present context is useful for elucidating the structure and topological organisation of the MC-receptors.
  • photoactive derivatives of the compounds of the invention are also part of the present invention.
  • preferably photoactive derivates of the compounds of the invention may also be made to incorporate an easily detectable group or label, such as e.g. a radioactive atom, a fluorescent group and/or biotin.
  • an easily detectable group or label such as e.g. a radioactive atom, a fluorescent group and/or biotin.
  • the compounds of the invention can be labeled with gamma and/or positron emitting isotope(s).
  • Such labeled compounds constitute very specific embodiments of the invention and may be administered systematically, or locally, to an animal, preferably a human.
  • These labeled compounds are useful for imaging the in vivo levels and/or localization of MC-receptors by the use of well known techniques among which may be mentioned Scintigraphy, Positron Emission Tomography (PET) and Single Photon Emission Computed Tomography (SPECT).
  • PET Positron Emission Tomography
  • SPECT Single Photon Emission Computed Tomography
  • Agonist and antagonist activities of the compounds of the invention may be evaluated by various methods known in the art. Examples of such methods are measurement of second messenger responses, in particular cAMP, the use of modified cell systems yielding colour reaction upon accumulation of second messenger elements such as cAMP, e.g. as described by Chen et al. 1995 (Anal Biochem. 1995, 226, 349-54), Cytosensor Microphysiometer techniques (see Boyfield et al. 1996), or the study of physiological effects caused by the compounds of the invention may be applied by using the compounds of the invention alone, or in combination with natural or synthetic MSH-peptides.
  • the compound of the invention may be delivered to the preferred site in the body, such as e.g. to the brain, by using a suitable drug delivery system.
  • Drug delivery systems are well known in the art.
  • the compound of the invention may be coupled to a carrier molecule making it lipophilic (see e.g. Toth, I., J. Drug. Targeting, 1994, 2, 217-239; Patel et al., Bioconjugate Chem., 1997, 8, 434-441 ).
  • Other technologies that can be used to deliver the compound of the invention to the desired site in the body are vector mediated carrier systems (see e.g. Pardridge, WM, Pharmacol. Toxicol. 1992, 71 , 3-10; Saito, Y et al. Proc.
  • the present invention also relates to a pro-drug which after the administration to an animal, including a human, is converted to a compound of the invention.
  • a pro-drug of the compound of the invention can be used for the same purposes as described above for the compounds of the invention, as well as is disclosed in the Examples given below.
  • the compound of the present invention can be covalently or non-covalently bound to one or several of other optional molecule(s) of any desired structure(s); the thus formed modified compound or complex can be used for the same purposes as described above for the compounds of the invention, as well as is disclosed in the Examples given below.
  • DMF N,N-Dimethylformamide
  • DMSO Dimethylsulfoxide
  • Fmoc-Cys(Trt)-OPfp 9-Fluorenylmethoxycarbonyl-S-trityl-L-cysteine pentafluorophenyl ester
  • HOAt 1-Hydroxy-7-azabenzotriazole
  • HOBt 1 -Hydroxybenzotriazole
  • Fmoc-Gly-OPfp 9-Fluorenylmethoxy- carbonyl-glycine pentafluorophenyl ester
  • Fmoc-Trp(Boc)-OH 9- Fluorenylmethoxycarbonyl-(Nln-tert-butyloxycarbonyl)-L-tryptophan
  • HATU O-(7-Azabenzotriazol-1-yl)-1 ,1 ,3,3-tetramethyluronium hexafluoro- phosphate
  • Fmoc-Arg(Pbf)-OH 9-Fluorenylmethoxycarbonyl-(N g -2,2,4,6,7- pentamethyldihydro benzofuran-5-sulfonyl)-L-arginine
  • Fmoc-D-Cha-OH 9-Fluoreny
  • MeCN Acetonitrile.
  • Fmoc-D-Nal-OH 9-Fluorenyl- methoxycarbonyl- ⁇ -2-naphtyl-D-alanine.
  • Fmoc-Nle-OPfp 9-Fluorenyl- methoxycarbonyl-L-norleucine pentafluorophenyl ester.
  • Example 1 Synthesis of cyclo(S-S)-[Ac-Cys 4 , D-Cha 7 , Cys-NH2 11 ] ⁇ -MSH(4- 10) trifluoroacetate (HS005).
  • the peptide sequence was assembled on a solid support using the Pioneer peptide synthesis system from PerSeptive Biosystems.
  • Example 2 Synthesis of cyclo(S-S)-[Ac-Cys 4 , D-Bpa 7 , Cys-NH 2 11 ] ⁇ -MSH(4- 11) trifluoroacetate. (HS006). The same approach as in Example 1 was used, the starting procedure being exactly identical.
  • Example 3 Synthesis of cyclo(S-S)-[Ac-Cys 4 , Arg 5 , D-Nal 7 , Cys-NH 2 11 ] ⁇ - MSH(4-11)ditrifluoracetate (HS007). The same approach as in Example 1 was used, the starting procedure being identical.
  • Example 4 Synthesis of cyclo(S-S)-(Ac-Cys 3 , L-Nle 4 , D-Nal 7 , Cys-NH 2 11 ) ⁇ - MSH(3-11 )trifluoracetate (HS010). The same approach as in Example 1 was used, the starting procedure being exactly identical.
  • Example 5 Synthesis of cyclo(S-S)-[Ac-Cys 4 , D-Phe 7 , Cys-NH 2 11 ] ⁇ -MSH(4- 11)trifluoracetate (HS963).
  • the peptide was synthesized using Fmoc based chemistry by the approach essentially as described in Example 1 , the intramolecular disulphide bond being formed by heating of the solution of the raw peptide in dimethylsulfoxide using the method described in Example 1.
  • the cyclic peptide was purified by HPLC and fractions, containing the main peak, were pooled and lyophilized. A white powder formed. Yield 14.6 mg (24 %).
  • Example 6 Synthesis of cyclo(S-S)-[Ac-Cys 4 , D-Nal 7 , Cys-NH 2 11 ] ⁇ -MSH(4-11) trifluoracetate (HS964).
  • the peptide was synthesized using Fmoc based chemistry by the approach essentially as described in Example 1 , the intramolecular disulphide bond being formed by heating of the solution of the raw peptides in dimethylsulfoxide, using the method described in Example 1.
  • the cyclic peptide was purified by HPLC and fractions, containing the main peak, were pooled and lyophilized. A white powder formed. Yield 17.5 mg (28 %).
  • Example 7 Synthesis of cyclo(S-S)-(Ac-L-Cys 4 ' , L-Ala 6 , D-Nal 7 , L-Cys 11 -NH 2 ) a-MSH 4 . 11 (HS011).
  • the peptide was synthesized on the 0.02 mmole scale using Fmoc based chemistry by the approach essentially as described in Example 1 , with the intramolecular disulphide bonds being formed by heating solutions of the peptides in dimethylsulfoxide using the method described in Example 1.
  • the cyclic peptide was purified by HPLC and fractions, containing the main peak, were pooled and lyophilized. White powder; yield 14.2 mg (67 %).
  • Example 8 Synthesis of cyclo(S-S)-(Ac-L-Nle 3 , L-Cys 4 , D-Nal 7 , L-Cys 11 -NH 2 ) a-MSH 4 . 11 (HS012).
  • the peptide was synthesized on the 0.02 mmole scale using Fmoc based chemistry by the approach essentially as described in Example 1 , with the intramolecular disulphide bond being formed by heating solutions of the peptide in dimethylsulfoxide using the method described in Example 1.
  • the cyclic peptide was purified by HPLC and fractions, containing the main peak, were pooled and lyophilized. White powder; yield 11.0 mg (44 %).
  • Example 9 Synthesis of cyclo(S-S)-(Ac-L-Cys 11 , D-Nal 14 , L-Cys 18 , L-Asp-NH 2 22 ) ⁇ -MSHn. 22 trifluoroacetate (HS014).
  • the peptide was synthesized on the 0.02 mmole scale using Fmoc based chemistry by the approach essentially as described in Example 1 with the intramolecular disulphide bond being formed by heating solutions of the peptide in dimethylsulfoxide using the method described in Example 1.
  • the cyclic peptide was purified by HPLC and fractions, containing the main peak, were pooled and lyophilized. A white powder formed. Yield 8.6 mg( 27 %).
  • Example 10 Assay of binding affinities of peptides for human MC-receptors. Expression of receptor clones. Human MC1- and MC5-receptor DNAs (Chhajlani and Wikberg 1992; Chhajlani et al., 1993), cloned into the expression vector pRc/CMV (InVitrogen Corp., USA), and human MC3- and human MC4-receptor DNAs (Gantz et al., 1993a & b), cloned into the expression vector pCMV/neo, were used. COS cells were grown and transfected with receptor clones as described (Schi ⁇ th et al. 1995, 1996b).
  • binding buffer Minimum Essential Medium with Earle's salts, 25 mM HEPES, pH 7.0, 0.2 % bovine serum albumin, 1 mM 1 ,10-phenanthroline, 0.5 mg per litre leupeptin and 200 mg per litre bacitracin
  • the cells were then incubated for 2 h at 37°C, with 0.1 ml binding buffer in each well containing [ 125 l][Nle 4 , D-Phe 7 ] ⁇ -MSH and appropriate concentrations of the peptide to be tested.
  • Example 11 Synthesis of cyclo(S-S)-(Ac-L-Cys 4 , D-Nal 7 , L-Asp 10 ,L-Cys- NH2 ⁇ 1 ) ⁇ -MSH4_ ⁇ 1 (HS009) was made essentially as described in Example 1. Yield 28.7%. Rf 0.55. k' 5.50(21 % MeCN in 0.1 % TFA). m/e 1185.
  • Example 12 Synthesis of cyclo(S-S)-(Ac-L-Cys 4 , L-Ala 6 , D-Nal 7 , L-Cys- NH2 ⁇ 1 ) ⁇ -MSH4--
  • Example 13 Synthesis of cyclo(S-S)-(Ac-L-Cys 4 , L-Pro 6 , D-Nal 7 , L-Cys- NH2 1 1 ) ⁇ -MSH4-i (HS015) was made essentially as described in Example 1. Yield 21.2%. Rf 0.70. k' 7.50 (25.2% MeCN in 0.1 % TFA). m/e 1086.
  • Example 14 Synthesis of cyclo(S-S)-(Ac-L-Cys 4 , L-Arg 5 , D-Nal 7 , L-Cys 1 1 . L-Asp 1 , L-Arg-L-Phe-NH2 13 ) ⁇ -MSH4- 3 (HS016) was made essentially as described in Example 1. Yield 18.0%. Rf 0.50. k' 3.08(19.8% MeCN in 0.1 % TFA). m/e 1572.
  • Example 15 Synthesis of cyclo(S-S)-(Ac-L-Cys 4 , L-Glu 6 , D-Nal 7 , L-Cys- NH2 1 ) ⁇ -MSH4_ ⁇ 1 (HS017) was made essentially as described in Example 1. Yield 23.2%. Rf 0.59. k' 6.31 (22.8% MeCN in 0.1 % TFA). m/e 1119.
  • Example 17 Synthesis of cyclo(S-S)-(Ac-L-Pro 8 , L-Cys 1 1 - D-Nal 14 - L-Cys 18 , L-Asp-NH2 2 2) ⁇ -MSH8-22 (HS019) was made essentially as described in Example 1. Yield 12.0%. Rf 0.55. k' 0.95(18% MeCN in 0.1 % TFA). m/e 1981.
  • Example 18 Synthesis of cyclo(S-S)-(Ac-L-Tyr 1 , L-Val 2 , L-Cys 3 , L-Nle 4 , D-Nal 7 , L-Cys 1 - L-Asp 12 , L-Arg-L-Phe-NH2 13 ) ⁇ -MSHi-13 (HS020) was made essentially as described in Example 1.Yield 14.5%. Rf 0.64. k' 3.84(25.8% MeCN in 0.1 % TFA). m/e 1922.
  • Example 19 Synthesis of cyclo(S-S)-(Ac-L-Cys 4 , Gly 6 , D-Nal 7 ,L-Cys-NH2 1 1 ) a-MSH4.11 (HS023) was made essentially as deschbed in Example 1. Yield 22.0%. Rf 0.66. k' 5.00 (20.4% MeCN in 0.1 % TFA). m/e 1047.
  • Example 20 Synthesis of cyclo(S-S)-(Ac-L-Cys 3 , L-Nle 4 , L-Arg 5 , D-Nal 7 , L-Cys-NH2 1 1 ) ⁇ -MSH4-i 1 (HS024) was made essentially as described in Example 1. Yield 20.1 %. Rf 0.63. k' 4.95(20.4% MeCN in 0.1 % TFA). m/e 1268.
  • Example 21 Synthesis of cyclo(S-S)-(Ac-L-Cys 1 1 > D-3,4-dichlorophenyl- alanine 14 .
  • Example 22 Synthesis of cyclo(S-S)-(Ac-L-Cys - D-4-fluorophenylalanine 14 - L-Cys 18 , L-Asp-NH2 22 ) ⁇ -MSHn-22 (HS029) was made essentially as described in Example 1. Yield 7.1 %. Rf 0.37. k' 0.22(15% MeCN in 0.1 % TFA). m/e 1532.
  • Example 23 Synthesis of cyclo(S-S)-(Ac-L-Cys 1 1 > D-4-nitrophenylalanine 14 .
  • L-Cys 18 , L-Asp-NH2 22 ) ⁇ -MSHn-22 (HS030) was made essentially as described in Example 1. Yield 7.6 %. Rf 0.40. k'0.53(13.8 % MeCN in 0.1 % TFA). m/e 1580.
  • Example 24 Synthesis of cyclo(S-S)-(Ac-L-Pro 8 , L-Cys 1 °. L-Nle 1 , L-Arg 12 , D-Nal 14 - L-Cys 8 , L-Asp-NH2 22 ) ⁇ -MSH8-22 (HS031 ) was made essentially as described in Example 1. Yield 6.7 %). Rf 0.44. k' 0.89(20.4% MeCN in 0.1 % TFA). m/e 1964.
  • Example 25 Synthesis of cyclo(S-S)-(Ac-L-Cys 1 °. L-Nle 1 , L-Arg 12 , D-Nal 14 - L-Cys 8 , L-Asp-NH2 22 ) ⁇ -MSH 0-22 (HS032) was made essentially as described in Example 1.Yield 15.0%). Rf 0.43. k' 0.61 (18% MeCN in 0.1 % TFA). m/e 1704.
  • Example 26 Synthesis of cyclo(S-S)-(Ac-L-Cys 3 , L-Nle 4 , D-Nal 7 , L-Cys 10 ) ⁇ -MSH3- 3 (HS040) was made essentially as described in Example 1. Yield 32.3 %. Rf 0.57. k' 1.0(18% MeCN in 0.1 % TFA). m/e 1506.
  • Example 27 Synthesis of cyclo(S-S)-(Ac-L-Cys 3 , L-Nle 4 , L-Arg 5 , D-Nal 7 , L-Cys-NH2 1 1 ) ⁇ -MSH 1- 1 (HS050) was made essentially as described in Example 1. Yield 15.3 %. Rf 0.69. k' 1.44(18.6% MeCN in 0.1 % TFA). m/e 1516.
  • Example 28 Synthesis of cyclo(S-S)-(Ac-L-Cys 3 , L-Nle 4 , D-Nal 7 , L-Cys- NH2 ) ⁇ -MSH 1- 1 (HS051 ) was made essentially as described in Example 1. Yield 13.3 %. Rf 0.70. k' 2.61 (22.8% MeCN in 0.1 % TFA). m/e 1489.
  • Example 29 Synthesis of cyclo(S-S)-(Ac-L-Cys 3 , L-Nle 4 , L-Arg 5 , D-Nal 7 , L-Cys-NH2 1 1 ) ⁇ -MSH3-i 1 (HS052) was made essentially as described in Example 1. Yield 30.0 %. Rf 0.70. k' 0.83(22.8% MeCN in 0.1 % TFA). m/e 1258.
  • Example 30 Synthesis of cyclo(S-S)-(Ac-L-Cys 3 , L-Nle 4 , L-Lys 5 , D-Nal 7 , L-Cys-NH2 1 1 ) ⁇ -MSH3-i 1 (HS053) was made essentially as described in Example 1. Yield 47.6%. Rf 0.62. k' 0.44(19.2% MeCN in 0.1 % TFA). m/e 1238.
  • Example 31 Synthesis of cyclo(S-S)-(Ac-L-Cys 3 , L-Phe 4 , L-Arg 5 , D-Nal 7 , L-Cys-NH2 1 ) ⁇ -MSH3-i 1 (HS054) was made essentially as described in Example 1. Yield 23.4 %. Rf 0.66. k' 3.00(15.6% MeCN in 0.1 % TFA). m/e 1300.
  • Example 32 Synthesis of cyclo(S-S)-(Ac-L-Cys 3 , L-Asn 4 , L-Arg 5 , D-Nal 7 , L-Cys-NH2 1 1 ) ⁇ -MSH3-i 1 (HS055) was made essentially as described in
  • Example 33 Synthesis of cyclo(S-S)-(Ac-L-Cys 3 , L-Nle 4 , L-Arg 5 , D-Nal 7 , L-Cys 1 1 ,L-Tyr-NH2 12 ) ⁇ -MSH3-i2 (HS058) was made essentially as described in Example 1. Yield 22.5%. Rf 0.67. k' 2.57(19.2% MeCN in 0.1 % TFA). m/e 1429.
  • Example 34 Synthesis of cyclo(S-S)-(Ac-L-Cys 3 , L-Nle 4 , L-Arg 5 , D-Nal 7 , L-Tyr 10 , L-Cys-NH2 1 ) ⁇ -MSH3-H (HS059) was made essentially as deschbed in Example 1. Yield 20%. Rf 0.65. k' 2.83(21.6% MeCN in 0.1 % TFA). m/e 1372.
  • Example 35 Synthesis of cyclo(S-S)-(Ac-L-Cys 3 , L-Nle 4 , L-Arg 5 , D-3,4- dichlorophenylalanine 7 , L-Cys-NH2 1 1 ) a-MSH3.11 (HS060) was made essentially as described in Example 1. Yield 30.3%. Rf 0.59. k' 2.50(18.0% MeCN in 0.1 % TFA). m/e 1285.
  • Example 36 Synthesis of cyclo(S-S)-(Ac-L-Cys 3 , L-Nle 4 , L-Arg 5 , D-4- fluorophenylalanine 7 , L-Cys-NH2 1 1 ) ⁇ -MSH3-i 1 (HS061 ) was made essentially as described in Example 1. Yield 21.6%. Rf 0.58. k' 2.23(19.2% MeCN in 0.1 % TFA). m/e 1234.
  • Example 37 Synthesis of cyclo(S-S)-(Ac-L-Cys 3 , L-Nle 4 , L-Arg 5 , D-4- nitrophenylalanine 7 , L-Cys-NH2 1 1 ) ⁇ -MSH3-i 1 (HS062) was made essentially as described in Example 1. Yield 36.0%. Rf 0.58. k' 2.11 (19.2% MeCN in 0.1 % TFA). m/e 1261.
  • Example 38 Synthesis of cyclo(S-S)-(Ac-L-Cys 3 , L-Nle 4 , L-Arg 5 , D-Cha 7 , L-Cys-NH2 1 ) ⁇ -MSH3-i 1 (HS063) was made essentially as described in
  • Example 1 Yield 27.8%. Rf 0.59. k' 2.11 (21.6% MeCN in 0.1 % TFA). m/e 1222.
  • Example 39 Synthesis of cyclo(S-S)-(Ac-L-Cys 3 , L-Nle 4 , L-Arg 5 , D-Bpa 7 ,
  • Example 40 Synthesis of cyclo(S-S)-(Ac-L-Cys 3 , L-Nle 4 , L-Arg 5 , D-L-1 ,2,3,4- tetrahydroisoquinoline-3-carboxylic acid 7 , L-Cys-NH2 1 1 ) ⁇ -MSH3_ ⁇ (HS069) was made essentially as described in Example 1. Yield 20.8%. Rf 0.57. k' 1.83(16.8% MeCN in 0.1 % TFA). m/e 1228.
  • Example 41 Synthesis of cyclo(S-S)-(Ac-L-Cys 1 1 .D-L-1 ,2,3,4-tetrahydro- isoquinoline-3-carboxylic acid 14 , L-Cys 18 , L-Asp-NH2 22 ) ⁇ -MSHn-22 (HS071 ) was made essentially as described in Example 1. Yield 8.2%. Rf 0.30. k' 1.33(13.8% MeCN in 0.1 % TFA). m/e 1525.
  • Example 42 Synthesis of cyclo(S-S)-(Ac-L-Cys 0 > L-Nle 1 1 , L-Arg 12 , D-Nal 14 , L-Cys 8 , L-Tyr-NH2 22 ) ⁇ -MSHn-22 (HS072) was made essentially as described in Example 1. Yield 19.1 %. Rf 0.48. k' 3.25(18% MeCN in 0.1 % TFA). m/e 1752.
  • Example 43 Synthesis of cyclo(S-S)-(Ac-L-Cys 0 > L-Nle 1 1 , L-Arg 12 , D-Nal 14 , L-Cys 8 , L-Tyr-NH2 22 ) ⁇ -MSHn-22 (HS072) was made essentially as described in Example 1. Yield 19.1 %. Rf 0.48. k' 3.25(18% MeCN in 0.1 % TFA). m/e 1752.
  • Example 43 Example 43
  • Example 44 Synthesis of cyclo(S-S)-(Ac-L-Cys 1 1 > D-4-cyanophenylalanine 14 , L-Cys 1 8 , L-As ⁇ -NH2 22 ) ⁇ -MSHn-22 (HS074) was made essentially as described in Example 1. Yield 9.1 %. Rf 0.38. k' 1.00(13.8% MeCN in 0.1 % TFA). m/e 1538.
  • Example 45 Synthesis of cyclo(S-S)-(Ac-L-Cys > D-4-iodophenylalanine 14 , L-Cys 18 , L-Asp-NH2 22 ) ⁇ -MSHi 1-22 (HS078) was made essentially as described in Example 1. Yield 10.7%. Rf 0.40. k' 1.67(16.2% MeCN in 0.1 % TFA). m/e 1639.
  • Example 46 Synthesis of cyclo(S-S)-(Ac-L-Cys 1 1 ⁇ D-4-bromophenylalanine 14 , L-Cys 1 8 , L-Asp-NH2 22 ) ⁇ -MSHn-22 (HS082) was made essentially as described in Example 1. Yield 10.7%. Rf 0.40. k' 1.67(16.2% MeCN in 0.1 % TFA). m/e 1639.
  • Example 47 Synthesis of cyclo(S-S)-(Ac-L-Cys 1 ⁇ D-4,4'-biphenylalanine 14 , L-Cys 1 8 , L-Asp-NH2 22 ) ⁇ -MSHn -22 (HS083) was made essentially as described in Example 1. Yield 17.0%. Rf 0.39. k' 1.94(17.4% MeCN in 0.1 % TFA). m/e 1589.
  • Example 48 Synthesis of cyclo(S-S)-(Ac-L-Cys 1 > D-pentafluorophenyl- alanine 14 , L-Cys 18 , L-Asp-NH2 22 ) ⁇ -MSHn-22 (HS084) was made essentially as described in Example 1. Yield 14.6%. Rf 0.38. k' 0.89(17.4% MeCN in 0.1 % TFA). m/e 1603.
  • Example 49 Synthesis of cyclo(S-S)-(Ac-L-Cys . D- ⁇ , ⁇ -diphenylalanine 14 , L-Cys 18 , L-Asp-NH2 22 ) ⁇ -MSHn-22 (HS085) was made essentially as described in Example 1. Yield 11.0%. Rf 0.37. k' 1.28(15% MeCN in 0.1 % TFA). m/e 1589.
  • Example 50 Synthesis of cyclo(S-S)-(Ac-L-Cys . D- ⁇ , ⁇ -diphenylalanine 14 , L-Cys 18 , L-Asp-NH2 22 ) ⁇ -MSHn-22
  • Example 51 Synthesis of cyclo(S-S)-(Ac-L-Cys 3 , L-Nle 4 , D-4-cyanophenyl- alanine 7 , L-Cys-NH2 1 1 ) a-MSH3.11 (HS087) was made essentially as described in Example 1.Yield 28.8%. Rf 0.60. k' 3,22(19.8% MeCN in 0.1 % TFA). m/e 1214.
  • Example 52 Synthesis of cyclo(S-S)-(Ac-L-Cys 3 , L-Nle 4 , D-4-iodophenyl- alanine 7 , L-Cys-NH2 1 1 ) ⁇ -MSH3-i 1 (HS091 ) was made essentially as described in Example 1. Yield 20.5%. Rf 0.65. k' 3.61 (22.8% MeCN in 0.1 % TFA). m/e 1315.
  • Example 53 Synthesis of cyclo(S-S)-(Ac-L-Cys 3 , L-Nle 4 , D-4-bromophenyl- alanine 7 , L-Cys-NH2 1 1 ) ⁇ -MSH3-H (HS095) was made essentially as described in Example 1. Yield 30.3%. Rf 0.64. k' 2.61 (22.2% MeCN in 0.1 % TFA). m/e 1268.
  • Example 54 Synthesis of cyclo(S-S)-(Ac-L-Cys 3 , L-Nle 4 , D-4,4'-biphenyl- alanine 7 , L-Cys-NH2 1 1 ) a-MSH3.11 (HS096) was made essentially as described in Example 1. Yield 23.3%. Rf 0.66. k' 2.94(25.2% MeCN in 0.1 % TFA). m/e 1265.
  • Example 55 Synthesis of cyclo(S-S)-(Ac-L-Cys 3 , L-Nle 4 , D-pentafluorophenyl- alanine 7 , L-Cys-NH2 1 1 ) ⁇ -MSH3_ ⁇ 1 (HS097) was made essentially as described in Example LYield 29.3%. Rf 0.64. k' 2.61 (22.8% MeCN in 0.1 % TFA). m/e 1269.
  • Example 56 Synthesis of cyclo(S-S)-(Ac-L-Cys 3 , L-Nle 4 , D- ⁇ , ⁇ -diphenyl- alanine 7 , L-Cys-NH2 1 1 ) a-MSH3.1 (HS098) was made essentially as described in Example 1. Yield 27.6%. Rf 0.66. k' 2.66(21 % MeCN in 0.1 % TFA). m/e 1265.
  • Example 57 Increase of food intake by HS014.
  • HS014 was dissolved in saline to provide the concentration of 2 nmol/microlitre.
  • the feeding experiments were performed starting from 7 th day after the surgery. On the day of the expehment the food was removed from wire baskets and the rats were injected intracerebroventricularly with saline or HS014 (0.1-10 nmol) over 1 min using a 33 gauge injector connected to the 50 microlitre Hamilton syringe and an infusion pump (World Precision Instruments, Sarasota, USA). The movement of an air bubble inside the PE20 polyethylene tubing confirmed the drug flow.
  • the needle was left in place for 30 seconds, then removed and the cannula closed with stylet and the rat returned to its home cage. All injections were carried out between 12.00-13.00 every third day and were given in randomised order. Food intake was then measured after 0.5, 1 , 2 and 4 h following the intracerebroventricular injection.
  • HS028 to increase body weight and rate of growth rats were operated upon under brietal (3%, 0.2 ml./100g) anaesthesia in order to implant a brain infusion kit connected to an osmotic minipump (Alzet, 2001 ) into the right lateral cerebral ventricle - 1.0 mm posterior, 1.5 mm lateral - to the bregma, for intracerebroventricular infusion.
  • Dental glas ionophor and a screw were used to secure the infusion kit in position.
  • the osmotic minipumps were placed subcutaneously in the midscapular region of the back. After 10 days of drug administration the osmotic minipumps were removed under light brietal anaesthesia.
  • Fig. 1 a Effect of administration of a single intracerebroventricular dose of between 0.1 and 10 nmol of HSO14 on food intake in free-feeding rats: data shown for each period of measurement;
  • Fig. 1 b Effect of administration of a single intracerebroventricular dose of between 0.1 and 10 nmol of HSO14 on cumulative food intake in free- feeding rats;
  • Fig. 2 Effect of continuous intracerebroventricular infusion of 0.07 or 0.7 micromol HS028 per hour on body weight (BWt) of rats. The infusion was started on December 17, 1997 and stopped on December 27, 1997. Controls were infused with the vehicle for HS028.
  • Chhajlani, V 1996, Distribution of cDNA for melanocortin receptor subtypes in human tissues, Biochem. Biophys. Res. Commun. 38, 73-80. Chhajlani, V and J E S. Wikberg, 1992, Molecular cloning and expression of the human melanocyte stimulating hormone receptor cDNA, FEBS Lett. 309, 417. Chhajlani, V et al., 1993, Molecular cloning of a novel human melanocortin receptor, Biochem.

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Abstract

L'invention concerne des peptides cycliques activant et/ou bloquant le récepteur MC, de formule générale (I) où LRG représente un amino-acide large, L représente un lieur à 26-29 membres liant LRG à Trp. Ces peptides sont utiles pour le traitement d'états liés à l'alimentation, le poids, la motivation, l'acquisition de connaissances, la mémoire, le comportement, l'inflammation, la température, la perception de la douleur, la pression artérielle, la fréquence cardiaque, le tonus vasculaire, la natriurie, la circulation sanguine dans le cerveau, la croissance du tissu nerveux, le développement placentaire, la synthèse et la libération d'aldostérone et la libération de thyroxine, la spermatogenèse, le poids ovarien, la sécrétion de prolactine et de FSH, l'hémorragie utérine chez les femmes, la sécrétion de sébum et de phéromone, le taux de glucose dans le sang, la croissance foetale in-utéro. Ces peptides sont également utiles dans le traitement d'autres phénomènes liés à la parturition et pour la neuroprotection. Les nouveaux peptides peuvent également être marqués et incorporés à des compositions pharmaceutiques.
PCT/SE1998/000270 1997-02-21 1998-02-16 Peptides cycliques selectifs vis-a-vis de sous-types de recepteurs msh WO1998037097A1 (fr)

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WO2000058361A1 (fr) * 1999-03-29 2000-10-05 The Procter & Gamble Company Ligands du recepteur de melanocortine
WO2000035952A3 (fr) * 1998-12-14 2000-10-19 Melacure Therapeutics Ab Composes permettant de reguler l'alimentation, la croissance et le poids corporel
WO2002000259A1 (fr) * 2000-06-27 2002-01-03 Taisho Pharmaceutical Co., Ltd. Agent therapeutique contre l'anxiete nevrotique ou la depression et derive de piperazine
US6693165B2 (en) 2000-01-18 2004-02-17 Merck & Co., Inc. Cyclic peptides as potent and selective melanocortin-4 receptor antagonists
WO2007008684A2 (fr) 2005-07-08 2007-01-18 Societe De Conseils De Recherches Et D'applications Scientifiques S.A.S. Ligands de recepteurs de melanocortine
WO2011005380A3 (fr) * 2009-06-12 2011-05-26 Stc. Unm Peptide hybride d'hormone stimulatrice des mélanocytes alpha conjuguées arg-gly-asp à utiliser dans le diagnostic et dans le traitement du mélanome, y compris le mélanome métastatique, et procédés afférents
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Cited By (17)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000035952A3 (fr) * 1998-12-14 2000-10-19 Melacure Therapeutics Ab Composes permettant de reguler l'alimentation, la croissance et le poids corporel
WO2000058361A1 (fr) * 1999-03-29 2000-10-05 The Procter & Gamble Company Ligands du recepteur de melanocortine
US6613874B1 (en) 1999-03-29 2003-09-02 The Procter & Gamble Company Melanocortin receptor ligands
RU2213098C2 (ru) * 1999-03-29 2003-09-27 Дзе Проктер Энд Гэмбл Компани Лиганды меланокортиновых рецепторов
US6951916B2 (en) 1999-03-29 2005-10-04 The Procter & Gamble Company Melanocortin receptor ligands
US6693165B2 (en) 2000-01-18 2004-02-17 Merck & Co., Inc. Cyclic peptides as potent and selective melanocortin-4 receptor antagonists
WO2002000259A1 (fr) * 2000-06-27 2002-01-03 Taisho Pharmaceutical Co., Ltd. Agent therapeutique contre l'anxiete nevrotique ou la depression et derive de piperazine
US6949552B2 (en) 2000-06-27 2005-09-27 Taisho Pharmaceutical Co., Ltd. Remedial agent for anxiety neurosis or depression and piperazine derivative
WO2007008684A2 (fr) 2005-07-08 2007-01-18 Societe De Conseils De Recherches Et D'applications Scientifiques S.A.S. Ligands de recepteurs de melanocortine
JP2009500426A (ja) * 2005-07-08 2009-01-08 ソシエテ・ドゥ・コンセイユ・ドゥ・ルシェルシュ・エ・ダプリカーション・シャンティフィック・エス・ア・エス メラノコルチン受容体のリガンド
EP1915168A4 (fr) * 2005-07-08 2010-03-31 Ipsen Pharma Ligands de recepteurs de melanocortine
US8039435B2 (en) 2005-07-08 2011-10-18 Ipsen Pharma S.A.S. Melanocortin receptor ligands
US8349797B2 (en) 2005-07-08 2013-01-08 Ipsen Pharma S.A.S. Ligands of melanocortin receptors
US9458195B2 (en) 2005-07-08 2016-10-04 Ipsen Pharma S.A.S. Melanocortin receptor ligands
US9850280B2 (en) 2005-07-08 2017-12-26 Ipsen Pharma S.A.S. Melanocortin receptor ligands
WO2011005380A3 (fr) * 2009-06-12 2011-05-26 Stc. Unm Peptide hybride d'hormone stimulatrice des mélanocytes alpha conjuguées arg-gly-asp à utiliser dans le diagnostic et dans le traitement du mélanome, y compris le mélanome métastatique, et procédés afférents
US9005575B2 (en) 2009-06-12 2015-04-14 Stc.Unm Arg-Gly-Asp-conjugated alpha-melanocyte stimulating hormone hybrid peptide for use in diagnosing and treating melanoma, including metastatic melanoma and methods related to same

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SE9700620D0 (sv) 1997-02-21
EP1025127A1 (fr) 2000-08-09
AU6127498A (en) 1998-09-09

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