Induction of novel agonist selectivity for the ADP-activated P2Y1 receptor versus the ADP-activated P2Y12 and P2Y13 receptors by conformational constraint of an ADP analog

The Journal of Pharmacology and Experimental Therapeutics
Mariya ChhatriwalaT Kendall Harden

Abstract

ADP is the cognate agonist of the P2Y1, P2Y12, and P2Y13 receptors. With the goal of identifying a high potency agonist that selectively activates the P2Y1 receptor, we examined the pharmacological selectivity of the conformationally constrained non-nucleotide analog (N)-methanocarba-2MeSADP [(1'S,2'R, 3'S,4'R,5'S)-4-[(6-amino-2-methylthio-9H-purin-9-yl)-1-diphosphoryloxymethyl]bicyclo[3.1.0]hexane-2,3-diol] among the three ADP-activated receptors. Each P2Y receptor was expressed transiently in COS-7 cells, and inositol lipid hydrolysis was quantified as a measure of receptor activity. In the case of the Gi-linked P2Y12 and P2Y13 receptors, a chimeric G protein, Galphaq/i, was coexpressed to confer a capacity of these Gi-linked receptors to activate phospholipase C. 2MeSADP (2-methylthio-ADP) was a potent agonist at all three receptors exhibiting EC50 values in the sub to low nanomolar range. In contrast, whereas (N)-methanocarba-2MeSADP was an extremely potent (EC50=1.2 +/- 0.2 nM) agonist at the P2Y1 receptor, this non-nucleotide analog exhibited no agonist activity at the P2Y12 receptor and very low activity at the P2Y13 receptor. (N)-Methanocarba-2MeSADP also failed to block the action of 2MeSADP at the P2Y12 and P2Y13 rece...Continue Reading

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Citations

Apr 12, 2008·Purinergic Signalling·Torsten SchönebergAngela Schulz
Apr 13, 2011·Purinergic Signalling·Kenneth A JacobsonStefano Costanzi
Mar 1, 2012·Purinergic Signalling·Kenneth A JacobsonZhan-Guo Gao
Jul 7, 2012·Purinergic Signalling·Sriram Govindan, Colin W Taylor
Jul 25, 2012·Purinergic Signalling·Zhan-Guo GaoKenneth A Jacobson
Dec 15, 2011·Proceedings of the National Academy of Sciences of the United States of America·Olivier PascualAlain Bessis
Jan 20, 2011·The Journal of Biological Chemistry·Esperanza JiménezBeatriz López-Corcuera
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Dec 24, 2004·Molecular Interventions·Kenneth A JacobsonZhan-Guo Gao
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Jul 5, 2008·Purinergic Signalling·Kenneth A JacobsonHyojin Ko
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Sep 4, 2010·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Zhan-Guo GaoKenneth A Jacobson
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Feb 11, 2020·British Journal of Pharmacology·Kenneth A JacobsonChrista E Müller

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