Identification of the first surrogate agonists for the G protein-coupled receptor GPR132

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Mohamed A. Shehata, Hanna Belcik Christensen, Vignir Isberg, Daniel Sejer Pedersen, Andreas Bender, Hans Bräuner-Osborne, David E. Gloriam

GPR132 is an orphan class A G protein-coupled receptor. It has been proposed to be activated by protons and to regulate apoptosis, atherosclerosis and inflammation, but these results are still preliminary. In the current work, we designed and screened a focused compound library using a β-arrestin recruitment assay, and thereby identified the first disclosed surrogate GPR132 agonist 1 with a potency of 3.4 μM. This constitutes the first available pharmacological tool for the in vitro characterization of the orphan receptor GPR132. The testing of 32 analogs furthermore identified a number of compounds with lower activity – of which six were agonists and two were antagonists – that were used to construct preliminary structure–activity relationships. Docking followed by a molecular dynamics simulation of compound 1 in a structural model of GPR132 displayed the putative interactions for the key ligand functionalities.
Original languageEnglish
JournalRSC Advances
Pages (from-to)48551-48557
Number of pages7
Publication statusPublished - 2015

Bibliographical note

M.A.S. was supported by a research scholarship from the Drug
Research Academy and Novo Nordisk A/S. D.E.G. and H.B.-O.
gratefully acknowledge nancial support by the Carlsberg
Foundation. D.E.G. and D.S.P. gratefully acknowledges nancial
support by the Lundbeck Foundation. Nils Nyberg is
acknowledged for help with NMR spectroscopy. NMR equipment
used in this work was purchased via a grant from The
Lundbeck Foundation (R77-A6742). H.B.-O. gratefully
acknowledges nancial support from the Danish Ministry of
Science, Innovation, and Higher Education

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