Structure-Based Design, Synthesis by Click Chemistry and Activity of Highly Selective A Adenosine Receptor Agonists.

2-Arylethynyl derivatives of (N)-methanocarba adenosine 5'-uronamides are selective AAR (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 AAR (based on the AAR agonist-bound structure) correctly predicted that a triazole would maintain the AAR selectivity, due to its ability to fit a narrow cleft in the receptor. The analogues with various and C2-aryltriazolyl substitution were synthesized and characterized in binding (K at hAAR 0.3 - 12 nM) and to demonstrate efficacy in controlling chronic neuropathic pain (chronic constriction injury). Among -methyl derivatives, a terminal pyrimidin-2-yl group in (MRS7116) increased duration of action (36% pain protection at 3 h) . -Ethyl 5-chlorothien-2-yl analogue (MRS7126) preserved efficacy (85% protection at 1 h) with short duration. Larger groups, e.g. (MRS7138, >90% protection at 1 and 3 h), greatly enhanced activity. Thus, we have combined structure-based methods and phenotypic screening to identify nucleoside derivatives having translational potential.