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

  • J Med Chem. 2021 May 13;64(9):5577-5592. doi: 10.1021/acs.jmedchem.0c02041.
Skye R Doering  1 ,  Katie Freeman  1 ,  Ginamarie Debevec  2 ,  Phaedra Geer  2 ,  Radleigh G Santos  3 ,  Travis M Lavoi  2 ,  Marc A Giulianotti  2 ,  Clemencia Pinilla  2 ,  Jon R Appel  2 ,  Richard A Houghten  2 ,  Mark D Ericson  1 ,  Carrie Haskell-Luevano  1
Affiliations
  • 1. Department of Medicinal Chemistry and Institute for Translational Neuroscience, University of Minnesota, Minneapolis, Minnesota 55455, United States.
  • 2. Florida International University, Port St. Lucie, Florida 34987, United States.
  • 3. Nova Southeastern University, 3301 College Avenue, Fort Lauderdale, Florida 33314, United States.
PMID: 33886285 DOI: 10.1021/acs.jmedchem.0c02041
Abstract

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.

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