Small molecule ligands for the melanocortin-4 receptor: pharmacology, biased signaling, and pharmacoperone potential.

The melanocortin-4 receptor (MC4R) is a critical regulator of energy homeostasis, affecting both energy intake and expenditure. It is also involved in regulating reproduction. Recent clinical success with peptide agonists has validated MC4R as a therapeutically actionable target. However, orally active small-molecule ligands would offer important advantages over injectable peptides. Small-molecule agonists may provide therapeutic opportunities for obesity and sexual dysfunction, whereas small-molecule antagonists may have utility in cachexia, anorexia, and related wasting states. In addition, some hydrophobic small molecules can function as pharmacoperones, rescuing trafficking-defective naturally occurring MC4R mutations and thereby offering a precision medicine avenue for a subset of monogenic obesity. Moreover, some MC4R ligands display biased signaling properties, suggesting that pathway-selective modulation may further expand the pharmacological and therapeutic landscape of this receptor. In this review, we summarize the major classes of small-molecule ligands reported for MC4R, with emphasis on their pharmacology, biased signaling, and pharmacoperone activity.