Dokument
| Titel: | Development of Fluorescent AF64394 Analogues Enables Real-Time Binding Studies for the Orphan Class A GPCR GPR3 |
| Autor: | Merlin Bresinsky |
| Weitere Verfasser: | Aida Shahraki; Peter Kolb; Steffen Pockes; Hannes Schihada |
| Weitere Beteiligte: | Journal of Medicinal Chemistry |
| Veröffentlicht: | 2023 |
| URI: | https://archiv.ub.uni-marburg.de/es/2023/0164 |
| DOI: | https://doi.org/10.1021/acs.jmedchem.3c01707 |
| URN: | urn:nbn:de:hebis:04-es2023-01646 |
| DDC: | Pharmakologie, Therapeutik |
| Titel (trans.): | Entwicklung von fluoreszierenden AF64394-Analoga ermöglicht Echtzeit-Bindungsstudien für den Orphan Class A GPCR GPR3 |
| Publikationsdatum: | 2023-11-13 |
| Lizenz: | https://creativecommons.org/licenses/by/4.0 |
| Schlagwörter: |
|---|
| Biolumineszenz-Resonanzenergietransfer,, fluorescence ligand, orphan GPCR, BRET, Fluoreszenzligand, BRET, GPCR, G-Protein gekoppelter Rezeptor, G protein-coupled receptor (GPCR), GPR3, GPR3 |
Summary:
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.
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