Issue 4, 2015

Structure-based design, synthesis by click chemistry and in vivo activity of highly selective A3 adenosine receptor agonists

Abstract

2-Arylethynyl derivatives of (N)-methanocarba adenosine 5′-uronamides are selective A3AR (adenosine receptor) agonists. Here we substitute a 1,2,3-triazol-1-yl linker in place of the rigid, linear ethynyl group to eliminate its potential metabolic liability. Docking of nucleosides containing possible short linker moieties at the adenine C2 position using a hybrid molecular model of the A3AR (based on the A2AAR agonist-bound structure) correctly predicted that a triazole would maintain the A3AR selectivity, due to its ability to fit a narrow cleft in the receptor. The analogues with various N6 and C2-aryltriazolyl substitution were synthesized and characterized in binding (Ki at hA3AR 0.3–12 nM) and in vivo to demonstrate efficacy in controlling chronic neuropathic pain (chronic constriction injury). Among N6-methyl derivatives, a terminal pyrimidin-2-yl group in 9 (MRS7116) increased duration of action (36% pain protection at 3 h) in vivo. N6-Ethyl 5-chlorothien-2-yl analogue 15 (MRS7126) preserved in vivo efficacy (85% protection at 1 h) with short duration. Larger N6 groups, e.g.17 (MRS7138, >90% protection at 1 and 3 h), greatly enhanced in vivo activity. Thus, we have combined structure-based methods and phenotypic screening to identify nucleoside derivatives having translational potential.

Graphical abstract: Structure-based design, synthesis by click chemistry and in vivo activity of highly selective A3 adenosine receptor agonists

Supplementary files

Article information

Article type
Concise Article
Submitted
22 Dec 2014
Accepted
20 Jan 2015
First published
02 Feb 2015

Med. Chem. Commun., 2015,6, 555-563

Structure-based design, synthesis by click chemistry and in vivo activity of highly selective A3 adenosine receptor agonists

D. K. Tosh, S. Paoletta, Z. Chen, S. Crane, J. Lloyd, Z. Gao, E. T. Gizewski, J. A. Auchampach, D. Salvemini and K. A. Jacobson, Med. Chem. Commun., 2015, 6, 555 DOI: 10.1039/C4MD00571F

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