The melanocortin (MC) receptor family comprises five known subtypes. MC3 and MC4 receptors and their natural peptide ligands, a-MSH and AgRP, are expressed within the CNS and are involved in feeding behavior and energy regulation.146,147 The localization of these receptors to amygdala148 suggests they may be involved in anxiety-related behaviors. a-MSH, the endogenous nonselective MC3/4 receptor agonist, given i.c.v. produces anxiogenic effects in various behavioral models including: increased separation distress vocalizations in the chick149,150; decreased exploratory behavior in the hole-board test in the rat151; reduced time spent in the open arms of the rat EPM151; and decreased licking in the Vogel conflict model in rat.152 Similarly, the synthetic nonselective MC3/4 agonist MTII is active in the Vogel conflict model in the rat152 and decreases the amount of time rats engage in social interaction.153 The MC4 receptor antagonist, HS014, and the more selective antagonist, MCL-0020, attenuate anorexia in the rat produced by immobilization/restraint stress, a possible measure of anxiety. MCL-0020 and MCL-0129 prevent swim stress-induced decreases in light area exploration in the light/dark exploration test in mice.152,155 Furthermore, MCL-0129, a selective MC4 receptor antagonist (Figure 12b), increased the amount of time rats spend in social interaction after a week of administration.153 Taken together, these preclinical findings suggest that MC4 antagonists may be useful in the treatment of anxiety disorders. The true utility of this target awaits proof of concept studies from human clinical trials.

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