Melanocortin 1 receptor

Diaryl-5-anilino-l,2,4-thiadiazoles are found to be potent and selective melanocortin-4-receptor (MC4) agonists for potential use for nerve regeneration and drug addiction <2003BMG185>. Compounds like 56 are being developed as cysteine protease inhibitors (see also Section 5.07.10) <2005JOC6230>. 

Lubrano-BertheUer, C., Le Stunff, C., Bougneres, P., and Vaisse, C. (2004) Clinical case seminar—a homozygous nuU mutation delineates the role of the melanocortin-4 receptor in humans. J. Clin. Endocrinol. Metab. 89, 2028-2032. 

Yeo, G. S. H., Lank, E. J., Farooqi, I. S., Keogh, J., Challis, B. G., and O RahiUy, S. (2003) Mutations in the human melanocortin-4 receptor gene associated with severe famUial obesity disrupts receptor function through multiple molecular mechanisms. Hum. Mol. Genet. 12, 561-574. 

Marsh, D. J., Hollopeter, G., Huszar, D., et al. (1999) Response of melanocortin-4 receptor-deficient mice to anorectic and orexigenic peptides. Nat. Genet. 21, 119-122. 

Vaisse, C., Clement, K., Durand, E., Hercberg, S., Guy-Grand, B., and Froguel, P. (2000) Melanocortin-4 receptor mutations are a frequent and heterogeneous cause of morbid obesity. J. Clin. Invest. 106, 253-262. 

Methoxyphenyl)-3,4-dihydro-27/-pyrimido[2,1 -a]isoquinoline exhibited good inhibition of melanocortin-4 receptors (01MIP5). /V-Methyl-11 -oxo-11 //-pyrido[2,l- ]quinazolin-7-carboxamide did not exhibit any MAO A and B inhibitory activities (97JMC2466). 

Serotonin. Serotonin central receptors appear to play a major role in glucose homeostasis. Experiments in obese mice have demonstrated that small doses of a classical serotonin agonist, metachlorophenylpiperazine (mCPP), markedly lower plasma insulin levels and increase insulin sensitivity, without affecting food intake, body weight or fat mass. The downstream target of the involved serotonin receptor appears to be melanocortin-4 receptors, in the arcuate nucleus of the hypothalamus. 

The increase in neuropeptide Y results in an increase in food intake. Obesity in the normal mouse results in an increase in plasma leptin, where increased levels of leptin at the leptin receptor (in the hypothalamus) provokes an increase in melanocortin (MSH). The increase in MSH in the brain pnjvokes an increase in stimulation of the melanocortin-4 receptor in the brain, which results in a decline in food intake- MSH is the hormone that binds to melanocortin receptors, where this interaction can be antagonized if agouti protein is allowed to contact the receptor. 

Melanocyte-stimulating hormone (MSH) is derived from pro-opiomelanocortin. It acts via melanocortin-4 receptors in the hypothalamus to inhibit feeding. It is thought to play an important role in mediating the action of leptin in the CNS (Tritos and Maratos-Flier 1999). 

Melanocortin 4 receptor V103I, many SNPs Morbid obesity, [71, 74-80]... 

Ste Marie L, Miura GI, Marsh DJ et al (2000) A metabolic defect promotes obesity in mice lacking melanocortin-4 receptors. Proc Nad Acad Sci U S A 97 12339-12344... 

Branson R, Potoczna N, Krai JG et al (2003) Binge eating as a major phenotype of melanocortin 4 receptor gene mutations. N Engl J Med 348 1096-1103... 

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