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

TY - JOUR

T1 - Identification of the first surrogate agonists for the G protein-coupled receptor GPR132

AU - Shehata, Mohamed A.

AU - Christensen, Hanna Belcik

AU - Isberg, Vignir

AU - Pedersen, Daniel Sejer

AU - Bender, Andreas

AU - Bräuner-Osborne, Hans

AU - Gloriam, David E.

N1 - Acknowledgements: 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

PY - 2015

Y1 - 2015

N2 - 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.

AB - 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.

U2 - 10.1039/c5ra04804d

DO - 10.1039/c5ra04804d

M3 - Journal article

SN - 2046-2069

VL - 5

SP - 48551

EP - 48557

JO - RSC Advances

JF - RSC Advances

ER -