College of Pharmacy
The melanocortin receptor (MCR) system consists of endogenous agonists, antagonists, G-protein coupled receptors, and auxiliary proteins that are involved in the regulation of complex physiological functions such as energy and weight homeostasis, feeding behavior, inflammation, sexual function, pigmentation, and exocrine gland function. The five melanocortin receptors (MC1-5R) are member of a G-protein coupled receptors (GPCRs) that activate the cAMP signal transduction pathway and are stimulated by the melanocortin agonists α, β, γ-melanocyte stimulating hormone (MSH) and adrenocorticotropin (ACTH). These receptors are antagonized by agouti (ASP) and agouti-related protein (AGRP), which are the only known endogenous antagonists of GPCRs identified to date.
Obesity continues to be a major health problem worldwide. Obesity-related conditions include heart disease, stroke, type 2 diabetes, and certain types of cancer. The human melanocortin-4 receptor (MC4R) has been identified by genetic studies as well as in individual morbidly obese humans to be a locus connected to obesity. More than 100 single nucleotide polymorphisms (SNPs) have been identified so far in obese and non-obese human adults and children. The MC4R is expressed primarily in the brain and regulates obesity, feeding behavior, and satiety, making it an attractive target for antiobesity drugs. The MC3R, which is expressed both centrally (including the hypothalamus) and peripherally, has been postulated to play fundamental roles in metabolism and energy homeostasis, as well as food intake. However, the physiological mechanism(s) of action for the MC3 receptor in the different tissues and the periphery are still unclear.
Selective and potent ligands on these receptors are highly desirable. But designing MC3R versus MC4R selective ligands have been proven a difficult task without the knowledge of structural and conformational features that differentiate SAR between the MC3 and MC4 receptor subtypes. One strategy to address this issue is to probe ligand structural features that can differentiate the ligand−receptor pharmacological profiles of the melanocortin receptors (MC1, MC3−5R).