The central relaxin-3/RXFP3 system plays important roles in stress responses, feeding, and motivation for reward. However, exploration of its therapeutic applications has been hampered by the lack of small molecule ligands and the cross-activation of RXFP1 in the brain and RXFP4 in the periphery. Herein, we report the first structure–activity relationship studies of a series of novel nonpeptide amidinohydrazone-based agonists, which were characterized by RXFP3 functional and radioligand binding assays. Several potent and efficacious RXFP3 agonists (e.g., 10d) were identified with EC50 values <10 nM. These compounds also had high potency at RXFP4 but no agonist activity at RXFP1, demonstrating > 100-fold selectivity for RXFP3/4 over RXFP1. In vitro ADME and pharmacokinetic assessments revealed that the amidinohydrazone derivatives may have limited brain permeability. Collectively, our findings provide the basis for further optimization of lead compounds to develop a suitable agonist to probe RXFP3 functions in the brain.
|Number of pages
|Journal of Medicinal Chemistry
|Published - Dec 23 2021
Bibliographical noteFunding Information:
This work was supported, in part, by the funding from the National Institute on Alcohol Abuse and Alcoholism (NIAAA, Grant R01AA028255 to C.J.), the National Institutes of Health; the Molecular Modeling and Biopharmaceutical Center at the University of Kentucky College of Pharmacy, the National Science Foundation (NSF, Grant CHE-1111761 to C.Z.); and the National Institutes of Health (P20 GM130456, UL1TR001998, T32 DA016176, and R01 DA039143 to C.Z.). The authors would also like to thank the University of Kentucky Center for Computational Sciences and Information Technology Services Research Computing for their support and use of the Lipscomb Compute Cluster and associated research computing resources.
© 2021 American Chemical Society
ASJC Scopus subject areas
- Molecular Medicine
- Drug Discovery