High-Throughput Screening Campaign Identified a Potential Small Molecule RXFP3/4 Agonist

Area of Science:

• Neuroscience
• Pharmacology
• Biochemistry

Background:

• The relaxin/insulin-like family peptide receptor 3 (RXFP3) is a G protein-coupled receptor primarily found in the brain.
• RXFP3 plays a crucial role in regulating appetite, metabolism, and emotional processing, making it a potential therapeutic target for central nervous system (CNS) disorders.

Purpose of the Study:

• To identify novel small molecule agonists for RXFP3 beyond its natural ligand, relaxin-3.
• To discover chemical probes for investigating RXFP3 and related receptors.

Main Methods:

• A high-throughput screening campaign involving 32,021 synthetic and natural compounds was performed.
• A cyclic adenosine monophosphate (cAMP) measurement-based assay was utilized to assess receptor activity.
• Primary and secondary screening, followed by dose-response studies, were conducted to validate hits.

Main Results:

• One compound, WNN0109-C011, was identified as a hit from the screening campaign.
• WNN0109-C011 demonstrated agonistic activity on human RXFP3 in cellular assays.
• The compound also exhibited cross-reactivity with human RXFP4.

Conclusions:

• WNN0109-C011 represents a novel chemical scaffold for developing RXFP3/4 agonists.
• This compound can serve as a valuable chemical probe for studying the physiological functions of RXFP3 and RXFP4.
• The findings open new avenues for therapeutic interventions targeting CNS diseases involving RXFP3 signaling.