Identification of the first surrogate agonists for the G protein-coupled receptor GPR132
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Identification of the first surrogate agonists for the G protein-coupled receptor GPR132. / Shehata, Mohamed A.; Christensen, Hanna Belcik; Isberg, Vignir; Pedersen, Daniel Sejer; Bender, Andreas; Bräuner-Osborne, Hans; Gloriam, David E.
I: RSC Advances, Bind 5, 2015, s. 48551-48557.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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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
VL - 5
SP - 48551
EP - 48557
JO - RSC Advances
JF - RSC Advances
SN - 2046-2069
ER -
ID: 138731434