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

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.