Orthogonal activation of the reengineered A3 adenosine receptor (neoceptor) using tailored nucleoside agonists.

Journal of Medicinal Chemistry
Zhan-Guo GaoKenneth A Jacobson

Abstract

An alternative approach to overcome the inherent lack of specificity of conventional agonist therapy can be the reengineering of the GPCRs and their agonists. A reengineered receptor (neoceptor) could be selectively activated by a modified agonist, but not by the endogenous agonist. Assisted by rhodopsin-based molecular modeling, we pinpointed mutations of the A(3) adenosine receptor (AR) for selective affinity enhancement following complementary modifications of adenosine. Ribose modifications examined included, at 3': amino, aminomethyl, azido, guanidino, ureido; and at 5': uronamido, azidodeoxy. N(6)-Variations included 3-iodobenzyl, 5-chloro-2-methyloxybenzyl, and methyl. An N(6)-3-iodobenzyl-3'-ureido adenosine derivative 10 activated phospholipase C in COS-7 cells (EC(50) = 0.18 microM) or phospholipase D in chick primary cardiomyocytes, both mediated by a mutant (H272E), but not the wild-type, A(3)AR. The affinity enhancements for 10 and the corresponding 3'-acetamidomethyl analogue 6 were >100-fold and >20-fold, respectively. 10 concentration-dependently protected cardiomyocytes transfected with the neoceptor against hypoxia. Unlike 10, adenosine activated the wild-type A(3)AR (EC(50) of 1.0 microM), but had no effect o...Continue Reading

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Citations

Mar 7, 2006·Nature Reviews. Drug Discovery·Kenneth A Jacobson, Zhan-Guo Gao
Oct 28, 2006·Nucleosides, Nucleotides & Nucleic Acids·Kenneth A JacobsonZhan-Guo Gao
Dec 11, 2007·Nucleosides, Nucleotides & Nucleic Acids·Lak Shin JeongHyung Ryong Moon
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Mar 14, 2017·Molecules : a Journal of Synthetic Chemistry and Natural Product Chemistry·Antonella Ciancetta, Kenneth A Jacobson
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Jul 2, 2021·Beilstein Journal of Organic Chemistry·Vineet VermaAshok K Prasad
Jan 5, 2013·Biochemistry·Dominik ThimmChrista E Müller
Dec 5, 2013·Chemical Reviews·Loránd Kiss, Ferenc Fülöp

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