Melanocortin-4 Receptor Antagonists for the Treatment of Depression and Anxiety Disorders

Derived from proopiomelanocortin by proteolytic processing, melanocortins have been implicated in a wide range of physiological processes. Melanocortins exert their physiological effects by binding to specific receptors on the surface of cell membranes. To date, five subtypes of melanocortin receptors (MC1 - MC5) have been identified, all of which are G-protein coupled receptor whose activation leads to increase in intracellular cyclic 3',5'-adenosine monophosphate formation. Of these, the MC4 receptor is expressed predominantly throughout the central nervous system, particularly, in areas related to stress responses and emotional states. Expression of the MC4 receptor is regulated by stress exposure. Reports also indicate that stimulation of the MC4 receptor activates the hypothalamus-pituitary-adrenal axis, and that the MC4 receptor mediates stress-related behaviors and anxiety in rodents. Recently developed selective MC4 receptor antagonists have demonstrated antidepressant and anxiolytic effects in several animal models of depression and anxiety. MC4 receptor antagonists are effective, particularly under conditions of high stress, which may be consistent with the etiology of depression and anxiety. This review describes the involvement of the MC4 receptor in stress response and discusses the potential value of MC4 receptor antagonists for the treatment of stress-related disorders such as depression and anxiety.