Chemical Probe Identification Platform for Orphan GPCRs Using Focused Compound Screening: GPR39 as a Case Example.

Area of Science:

• Pharmacology
• Biochemistry
• Drug Discovery

Background:

• Orphan G protein-coupled receptors (oGPCRs) lack identified endogenous ligands, hindering their study and therapeutic development.
• Transgenic animal models suggest oGPCRs play roles in various diseases, making them attractive drug targets.
• Chemical probes are essential for interrogating oGPCR signaling pathways and validating their therapeutic potential.

Purpose of the Study:

• To develop a novel platform for identifying chemical probe compounds against oGPCRs.
• To discover the first small molecule agonists for the GPR39 receptor.
• To investigate the functional effects of GPR39 agonists in cellular models.

Main Methods:

• Screening of GPCR-focused compound libraries against a set of oGPCR targets.
• Utilizing a novel chemical probe identification platform.
• Assessing compound activity through intracellular calcium mobilization assays in recombinant and native cells.
• Evaluating the effect of compounds on glucose-stimulated insulin secretion in human islet preparations.

Main Results:

• The platform successfully identified small molecule agonists for GPR39.
• Compound 1 demonstrated GPR39-specific intracellular calcium mobilization.
• Compound 1 did not enhance glucose-stimulated insulin secretion in human islets.
• This represents the first report of small molecule agonists for GPR39.

Conclusions:

• The developed platform is effective for discovering chemical probes for oGPCRs.
• The identified GPR39 agonists serve as valuable tools for further research into GPR39 function.
• These findings open new avenues for therapeutic strategies targeting GPR39 in metabolic diseases.