Journal
JOURNAL OF MEDICINAL CHEMISTRY
Volume 66, Issue 21, Pages 15025-15041Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.jmedchem.3c01707
Keywords
-
Categories
Ask authors/readers for more resources
In this study, a signaling pathway-independent readout of compound-GPR3 interaction was developed, providing new cues for the pharmacological manipulation of GPR3 activity. This has significant implications for the future development of drugs targeting these pharmacologically attractive oGPCRs.
The orphan G protein-coupled receptor (oGPCR) GPR3 represents a potential drug target for the treatment of Alzheimer's disease and metabolic disorders. However, the limited toolbox of pharmacological assays hampers the development of advanced ligands. Here, we developed a signaling pathway-independent readout of compound-GPR3 interaction. Starting from computational binding pose predictions of the most potent GPR3 ligand, we designed a series of fluorescent AF64394 analogues and assessed their suitability for BRET-based binding studies. The most potent ligand, 45 (UR-MB-355), bound to GPR3 and closely related receptors, GPR6 and GPR12, with similar submicromolar affinities. Furthermore, we found that 45 engages GPR3 in a distinct mode compared to AF64394, and coincubation studies with the GPR3 agonist diphenyleneiodonium chloride revealed allosteric modulation of 45 binding. These insights provide new cues for the pharmacological manipulation of GPR3 activity. This novel binding assay will foster the development of future drugs acting through these pharmacologically attractive oGPCRs.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available