High-Throughput Screening Campaign Identified a Potential Small Molecule RXFP3/4 Agonist
Guangyao Lin,
Yang Feng,
Xiaoqing Cai,
Caihong Zhou,
Lijun Shao,
Yan Chen,
Linhai Chen,
Qing Liu,
Qingtong Zhou,
Ross A.D. Bathgate,
Dehua Yang,
Ming-Wei Wang
Affiliations
Guangyao Lin
The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
Yang Feng
The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
Xiaoqing Cai
The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
Caihong Zhou
The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
Lijun Shao
University of Chinese Academy of Sciences, Beijing 100049, China
Yan Chen
Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
Linhai Chen
The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
Qing Liu
The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
Qingtong Zhou
Department of Pharmacology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China
Ross A.D. Bathgate
Florey Institute of Neuroscience and Mental Health and Department of Biochemistry and Pharmacology, The University of Melbourne, Parkville, VIC 3052, Australia
Dehua Yang
The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
Ming-Wei Wang
The National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
Relaxin/insulin-like family peptide receptor 3 (RXFP3) belongs to class A G protein-coupled receptor family. RXFP3 and its endogenous ligand relaxin-3 are mainly expressed in the brain with important roles in the regulation of appetite, energy metabolism, endocrine homeostasis and emotional processing. It is therefore implicated as a potential target for treatment of various central nervous system diseases. Since selective agonists of RXFP3 are restricted to relaxin-3 and its analogs, we conducted a high-throughput screening campaign against 32,021 synthetic and natural product-derived compounds using a cyclic adenosine monophosphate (cAMP) measurement-based method. Only one compound, WNN0109-C011, was identified following primary screening, secondary screening and dose-response studies. Although displayed agonistic effect in cells overexpressing the human RXFP3, it also showed cross-reactivity with the human RXFP4. This hit compound may provide not only a chemical probe to investigate the function of RXFP3/4, but also a novel scaffold for the development of RXFP3/4 agonists.
