Discovery of Nanomolar Melanocortin‑3 Receptor (MC3R)-Selective Small Molecule Pyrrolidine Bis-Cyclic Guanidine Agonist Compounds Via a High-Throughput “Unbiased” Screening Campaign

The
central melanocortin-3 and melanocortin-4 receptors (MC3R,
MC4R) are key regulators of body weight and energy homeostasis. Herein,
the discovery and characterization of first-in-class small molecule
melanocortin agonists with selectivity for the melanocortin-3 receptor
over the melanocortin-4 receptor are reported. Identified via “unbiased”
mixture-based high-throughput screening approaches, pharmacological
evaluation of these pyrrolidine bis-cyclic guanidines resulted in
nanomolar agonist activity at the melanocortin-3 receptor. The pharmacological
profiles at the remaining melanocortin receptor subtypes tested indicated
similar agonist potencies at both the melanocortin-1 and melanocortin-5
receptors and antagonist or micromolar agonist activities at the melanocortin-4
receptor. This group of small molecules represents a new area of chemical
space for the melanocortin receptors with mixed receptor pharmacology
profiles that may serve as novel lead compounds to modulate states
of dysregulated energy balance.