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Definition
Melanin-concentrating hormone (MCH) is a hypothalamic neuropeptide that plays a role in the modulation of food intake and mood.

Discovery
MCH is a cyclic nonadecapeptide originally isolated from salmon pituitary and involved in food intake and body color change in fish. Its effects are mediated by two receptors belonging to the super family of G protein coupled receptors (GPCR): MCHR1 (originally SLC-1/ GPR24) and MCH2R (SLT/S643b), the latter is found in primates but not in rodents 1, 2, 3 . The first reported selective, high affinity MCHR1 antagonist, SNAP 7941, had acute antidepressant and anxiolyticlike effects in the rat forced swim test (FST) and social interaction tests and the guinea pig maternal separationinduced vocalization test. Two new MCHR1 antagonists, ATC0065 and ATC0175, were also shown to have anxiolytic- and antidepressant-like activity in rodents 4, 5 .

Structural Characteristics
Many pharmaceutical companies have described MCH-R1 antagonists that have appeared over last few year. These are basically small molecules. A novel MCH receptor antagonist, T-226296, a (-) enantiomer of N-[6-(dimethylamino)-methyl]-5,6,7,8-tetrahydro-2-naphthalenyl]-4'-fluoro[1,1'-biphenyl]-4-carboxamide. T-226296 exhibited high affinity for cloned human and rat MCH receptors (SLC-1) in receptor binding assays (IC50=5.5+/-0.12 nM for human SLC-1; 8.6+/-0.32 nM for rat SLC-1). T-226296 had high selectivity over other receptors, including the second subtype of the MCH receptor, SLT (MCH2), transporters and ion channels 6.

Mode of action
In Chinese hamster ovary (CHO) cells expressing human SLC-1, T-226296 reversed the MCH-mediated inhibition of forskolin-stimulated cAMP accumulation, inhibited MCH-induced intracellular Ca2+ increase, and also inhibited MCH-stimulated arachidonic acid release 6.The antagonist radioligand [3H]SNAP 7941 exhibit saturable, high affinity specific binding to membranes from PEAKRAPID 293 cells expressing the mouse MCHR1 . Functional antagonism of MCH-evoked [3H]inositol phosphate formation in HEK 293 cells stably expressing the rat MCHR1. SNAP 94847 produced concentration-dependent dextral shifts in the concentration curve to MCH, with a progressive reduction in the maximal response 7. Results suggest that SNAP 94847 is a novel, high affinity selective antagonist at the MCHR1 with neurogenesis-independent actions in mouse behavioral models that differentiate it from classic anxiolytic and antidepressant drugs. In vitro functional studies show it to be a high affinity antagonist of MCH-evoked inositol phosphate formation, producing dextral shifts accompanied by a reduction of the maximal effect in the concentration-effect curve to MCH, consistent with an orthosteric-insurmountable antagonist interaction 7.

Functions
MCHR1 antagonist target for antidepressant development as it is observed a decrease of immobility in the FST in rats after the injection of antagonist.  Specific MCHR1 antagonist, SNAP 94847, may be more effective for the treatment of anxiety disorders than for depression. One potential advantage of MCHR1 antagonists for the treatment of anxiety may be an acute onset of action compared with the delayed onset of therapeutic efficacy of other antagonist 7.  In rats, oral administration of T-226296 (30 mg/kg) almost completely suppressed the food intake induced by intracerebroventricular injection of MCH indicating that T-226296 is a novel, orally active and selective MCH receptor antagonist which is involved in physiology and pathophysiology of MCH-SLC-1 signaling 6. MCH activates stress responses and induces depressive- and anxiety-like behaviours, while the blockade of MCH1 receptors results in antidepressant and anxiolytic effects in various rodent models. Moreover, MCH may decrease reward activity while increasing hypothalamus-pituitary adrenal axis activity, both of which may underlie the neurochemical mechanisms of the depression and anxiety-like effects induced by MCH. The effects of MCH1 receptor antagonists in animal models, together with their rapid onset of effect and lack of adverse CNS effects, suggest that they have potential for treatments of depression and anxiety disorders 8.

References

1.     Kawauchi H, Kawazoe I, Tsubokawa M, Kishida M, and Baker BI (1983). Characterization of melanin-concentrating hormone in chum salmon pituitaries. Nature, 305:321–323.

2.     Bachner D, Kreienkamp H, Weise C, Buck F, and Richter D (1999). Identification of melanin-concentrating hormone (MCH) as the natural ligand for the orphan somatostatin-like receptor 1 (SLC-1). FEBS Lett., 457:522–524.

3.     Sailer AW, Sano H, Zeng Z, McDonald TP, Pan J, Pong SS, Feighner SD, Tan CP, Fukami T, Iwaasa H  (2001). Identification and characterization of a second melanin-concentrating hormone receptor, MCH-2R. PNAS., 98:7564–7569.

4.     Borowsky B, Durkin MM, Ogozalek K, Marzabadi MR, DeLeon J, Lagu B, Heurich R, Lichtblau H, Shaposhnik Z, Daniewska l. (2002). Antidepressant, anxiolytic and anorectic effects of a melanin-concentrating hormone-1 receptor antagonist. Nat Med., 8:825–830.

5.     Chaki S, Funakoshi T, Hirota-Okuno S, Nishiguchi M, Shimazaki T, Iijima M, Grottick AJ, Kanuma K, Omodera K, Sekiguchi Y (2005). Anxiolytic- and antidepressant-like profile of ATC0065 and ATC0175: nonpeptidic and orally active melanin-concentrating hormone receptor 1 antagonists. J Pharmacol Exp., 313: 831–839.

6.     Takekawa S, Asami A, Ishihara Y, Terauchi J, Kato K, Shimomura Y, Mori M, Murakoshi H, Kato K, Suzuki N, Nishimura O, Fujino M (2002). "T-226296: a novel, orally active and selective melanin-concentrating hormone receptor antagonist". European Journal of Pharmacology, 438(3):129–135.

7.     David DJ, Klemenhagen KC, Holick KA, Saxe MD, Mendez I, Santarelli L, Craig DA, Zhong H, Swanson CJ, Hegde LG, Ping XI, Dong D, Marzabadi MR, Gerald CP, Hen R (2007). "Efficacy of the MCHR1 antagonist N-[3-(1-{[4-(3,4-difluorophenoxy)phenyl]methyl}(4-piperidyl))-4-methylphenyl]-2-methylpropanamide (SNAP 94847) in mouse models of anxiety and depression following acute and chronic administration is independent of hippocampal neurogenesis". The Journal of Pharmacology and Experimental Therapeutics, 321(1):237–248.

8.     Shimazaki T, Yoshimizu T, Chaki S (2006). "Melanin-concentrating hormone MCH1 receptor antagonists: a potential new approach to the treatment of depression and anxiety disorders". CNS Drugs., 20(10):801–811.

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