Designing G-protein Associated Melanocortin Receptor antagonists. Melanocortin-2 receptor (MC2R, Fig ) is a G protein coupled receptor selectively agonized by the adrenocorticotropic hormone (ACTH) and exclusively expressed in the adrenal gland . Autosomal mutations of MC2R result in glucocorticoid deficiency and require exogenous glucocorticoid administration . ACTH overexpression leads to Cushing's disease and congenital adrenal hyperplasia (CAH) . As a result, small molecules that antagonize MC2R serve as potential tool compounds for understanding Cushing's disease and CAH biology, as well as points of departure for potential therapeutics. There are no therapeutics treating Cushing's disease or CAH; Crinetics Pharmaceuticals is conducting phase 1b/2a clinical trials with an MC2R antagonist .