The melanocortins (MCs) regulate diverse physiological functions through membrane MC receptors (MCRs). Five MCRs have been cloned and characterized to date. The physiological roles of these receptors are now known for four of the five subtypes. The MC1R is involved in epidermal melanin pigmentation and animal coat coloration. The MC2R plays a role in fat cell lipolysis and adrenal steroidogenesis. The MC3R has been implicated in cardiovascular control and natriuresis, but remains to be identified. The MC4R has been reported to be important in feeding behavior and weight homeostasis and the MC5R is involved in exocrine gland function. Two proteins have been identified as antagonizing MCR subtypes and are the only known naturally occurring antagonists of G-protein-coupled receptors: agouti and the agouti- related protein (AGRP). AGRP is a prime candidate to function as a naturally occurring antagonist of the MCR(s) located in the brain. Initial approaches to the design of synthetic MC ligands involved determining which hormone amino acids were important for biological activity, followed by side-chain cyclizations and incorporation of D amino acids, and a variety of other modifications. Two MC analogues, melanotan I (MT-I) and melanotan II (MT- II), possessing the attributes of superpotency and prolonged biological activity, have been licensed for clinical trials in humans for several novel potential uses. MT-I is being studied for its potential use in tanning of the skin, and MT-II in the diagnosis and treatment of erectile dysfunction.
|Original language||English (US)|
|Number of pages||9|
|Journal||Drug News and Perspectives|
|State||Published - Jan 1 1999|