The
melanocortin family of receptors (MC 1-5R) and their endogenous
peptide ligands (alpha, beta,
gamma- MSH and
ACTH) have been implicated in the control of a wide variety of behavioral and physiological functions including the homeostatic control of food intake and
body weight. In rodent models,
melanocortin agonists including the nonselective
peptide MTII have been shown to decrease food intake and
body weight while antagonists such as
SHU9119 and AGRP have been shown to stimulate food intake and increase
body weight. Deletion of either the MC3R or MC4R in mice was found to be associated with
obesity although
hyperphagia was only observed in the MC4R deficient mice. Similarly in humans, inactivating mutations of the MC4R have been found in as many as six percent of obese individuals. The suggestion from these findings that activation of MC4Rs would have an
anorectic effect in humans has resulted in efforts to produce selective agonists for the treatment of
obesity. Over the past decade, efforts to develop MC4R selective small molecule and
peptide agonists have been met with fractional success. Many small molecule agonists have been identified; however, few have been shown to have activity in vivo. While their use as
therapeutics may have limitations, selective and potent
peptide agonists have been shown by several investigators to decrease food intake and
body weight in rodent models. The subject of the current review is to examine the progress made to date on producing both small molecule and
peptide MC4R agonists as potential
therapeutics for
obesity.