Inverse agonists and biased ligands for the G protein-coupled receptor 3 (GPR3) – an integrative approach

• Applicants: Professor Dr. Peter Gmeiner; Dr. Dorothée Weikert
• Subject Area: Pharmacy
• Term: since 2025
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 567151554

The orphan G protein-coupled receptor 3 (GPR3) is widely expressed in the central nervous system but is also present in peripheral tissues. GPR3 constitutively activates Gs proteins, resulting in the accumulation of cAMP. Interestingly, GPR3 is involved in the regulation of gamma-secretase via the recruitment of ß-arrestins, thereby mediating the amyloidogenic proteolysis of amyloid precursor protein. GPR3 is therefore a potential therapeutic target for the treatment of Alzheimer's disease. This project aims to better understand the functional and structural properties of GPR3. Guided by this understanding, we will discover novel lead compounds that modulate the activity of GPR3. Our preliminary results have been directed towards the determination of an active state structure of GPR3 bound to its agonist oleic acid ethanolamide and a structure in the presence of an inverse agonist, where the inverse agonist engages an allosteric binding pocket of GPR3, unexpectedly stabilizing a GPR3 homodimer. Our research will combine structure-based design, lead optimization, and in silico docking with structural and in vitro pharmacological studies of pathway-specific ligand modulation and receptor dimerization. This approach will allow us to understand the crucial ligand-receptor interactions and their impact on GPR3-mediated signaling, and to effectively modulate these with novel inverse agonists and biased ligands. Overall, the project will significantly contribute to the development of new molecular tools to further delineate the biology of GPR3 and to novel lead candidates for GPR3 as a promising target in Alzheimer's disease.

• DFG Programme: Research Grants