have been shown to decrease food consumption and weight in rodents. Peptide derivatives of a-MSH, which are functional MC-4R antagonists, as well as agouti and AGRP, have been shown to increase food consumption and weight in rodents. In addition, genetic studies have shown that the melanocortin-4 receptor (MC-4R) has a critical role in the regulation of food consumption and metabolism in humans, as well as mice. Since there are five known melanocortin receptors (MCR-1, MCR-2, MCR-3, MCR-4, and MCR-5), with relatively high similarity at the amino acid level, identification of selective MCR-4 agonist could be difficult.

Recently a number of research groups have claimed to have some success in identifying specific small molecule agonists for MCR-4 (26,27). Most of these compounds have evolved from peptide based 9 approaches but some non-peptide based compounds 10 and H have also been discovered (28,29). 2,3-Diaryl-5-anilino[1,2,4,]thiadiazoles agonists have been reported to effect feeding behavior when given intraperitoneally, but not orally, in rats (30). Aside from concerns over the pharmacokinetic properties of peptide based therapeutics, and therapeutic liabilities of agonists in general, there have been reports of erectogenic effects in rodents which could conceivably limit the utility of MCR-4 therapeutics (31).

Neuropeptide Y Receptors - Neuropeptide Y (NPY) is a small (36-amino acid) amidated peptide that has potent orexigenic effects when injected directly (intracerebroventicular administration) into the brains of rats (31). To-date, at least six NPY receptors have been identified. The NPY receptors, Y1 and Y5, are most often identified as the targets for anti-obesity therapeutics. There is much conflicting evidence on the potential utility of NPY receptors, but with the recent demonstration that infusion of the NPY Y2 receptor peptidic agonist PYY3-36 reduced food intake

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