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

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

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.

Figures
Products