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Journal Article

Development of a Potent and Selective G2A (GPR132) Agonist

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Alnouri,  Mohamad Wessam
Pharmacology, Max Planck Institute for Heart and Lung Research, Max Planck Society;

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Offermanns,  Stefan
Pharmacology, Max Planck Institute for Heart and Lung Research, Max Planck Society;

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Citation

Hernandez-Olmos, V., Heering, J., Marinescu, B., Schermeng, T., Ivanov, V. V., Moroz, Y. S., et al. (2024). Development of a Potent and Selective G2A (GPR132) Agonist. JOURNAL OF MEDICINAL CHEMISTRY. doi:10.1021/acs.jmedchem.3c02164.


Cite as: https://hdl.handle.net/21.11116/0000-000F-84C5-D
Abstract
G protein-coupled receptor G2A was postulated to be a promising target for the development of new therapeutics in neuropathic pain, acute myeloid leukemia, and inflammation. However, there is still a lack of potent, selective, and drug-like G2A agonists to be used as a chemical tool or as the starting matter for the development of drugs. In this work, we present the discovery and structure-activity relationship elucidation of a new potent and selective G2A agonist scaffold. Systematic optimization resulted in (3-(pyridin-3-ylmethoxy)benzoyl)- D-phenylalanine (T-10418) exhibiting higher potency than the reference and natural ligand 9-HODE and high selectivity among G protein-coupled receptors. With its favorable activity, a clean selectivity profile, excellent solubility, and high metabolic stability, T-10418 qualifies as a pharmacological tool to investigate the effects of G2A activation.