2. Academic Validation
  3. Discovery and Characterization of the First Nonpeptide Antagonists for the Relaxin-3/RXFP3 System

Discovery and Characterization of the First Nonpeptide Antagonists for the Relaxin-3/RXFP3 System

  • J Med Chem. 2022 Jun 9;65(11):7959-7974. doi: 10.1021/acs.jmedchem.2c00508.
Elaine A Gay 1,  Dongliang Guan 1,  Kalynn Van Voorhies 2,  Vineetha Vasukuttan 1,  Kelly M Mathews 1,  Joyce Besheer 2 3,  Chunyang Jin 1
Affiliations

Affiliations

  • 1 Center for Drug Discovery, Research Triangle Institute, Research Triangle Park, Research Triangle Park, North Carolina 27709, United States.
  • 2 Bowles Center for Alcohol Studies, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
  • 3 Department of Psychiatry, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States.
PMID: 35594150 DOI: 10.1021/acs.jmedchem.2c00508
Abstract

The neuropeptide relaxin-3/RXFP3 system is involved in many important physiological processes such as stress responses, appetite control, and motivation for reward. To date, pharmacological studies of RXFP3 have been limited to peptide ligands. In this study, we report the discovery of the first small-molecule antagonists of RXFP3 through a high-throughput screening campaign. Focused structure-activity relationship studies of the hit compound resulted in RLX-33 (33) that was able to inhibit relaxin-3 activity in a battery of functional assays. RLX-33 is selective for RXFP3 over RXFP1 and RXFP4, two related members in the relaxin/Insulin superfamily, and has favorable pharmacokinetic properties for behavioral assessment. When administered to rats intraperitoneally, RLX-33 blocked food intake induced by the RXFP3-selective agonist R3/I5. Collectively, our findings demonstrated that RLX-33 represents a promising antagonist scaffold for the development of drugs targeting the relaxin-3/RXFP3 system.

Figures
Products