title: Structure-Based Design, Synthesis by Click Chemistry andin VivoActivity of Highly Selective A3Adenosine 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 variousN6and C2-aryltriazolyl substitution were synthesized and characterized in binding (Kiat hA3AR 0.3 - 12 nM) andin vivoto demonstrate efficacy in controlling chronic neuropathic pain (chronic constriction injury). AmongN6-methyl derivatives, a terminal pyrimidin-2-yl group in9(MRS7116) increased duration of action (36% pain protection at 3 h)in vivo.N6-Ethyl 5-chlorothien-2-yl analogue15(MRS7126) preservedin vivoefficacy (85% protection at 1 h) with short duration. LargerN6groups, e.g.17(MRS7138, >90% protection at 1 and 3 h), greatly enhancedin vivoactivity. Thus, we have combined structure-based methods and phenotypic screening to identify nucleoside derivatives having translational potential.
authors.affiliation: Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892 USA.
authors.forename: Dilip K
authors.initials: DK
authors.lastname: Tosh
authors.affiliation: Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892 USA.
authors.forename: Silvia
authors.initials: S
authors.lastname: Paoletta
authors.affiliation: Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, St. Louis, Missouri 63104 USA.
authors.forename: Zhoumou
authors.initials: Z
authors.lastname: Chen
authors.affiliation: Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892 USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Crane
authors.affiliation: Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892 USA.
authors.forename: John
authors.initials: J
authors.lastname: Lloyd
authors.affiliation: Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892 USA.
authors.forename: Zhan-Guo
authors.initials: ZG
authors.lastname: Gao
authors.affiliation: Department of Pharmacology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, Wisconsin 53226 USA.
authors.forename: Elizabeth T
authors.initials: ET
authors.lastname: Gizewski
authors.affiliation: Department of Pharmacology, Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, Wisconsin 53226 USA.
authors.forename: John A
authors.initials: JA
authors.lastname: Auchampach
authors.affiliation: Department of Pharmacological and Physiological Science, Saint Louis University School of Medicine, St. Louis, Missouri 63104 USA.
authors.forename: Daniela
authors.initials: D
authors.lastname: Salvemini
authors.affiliation: Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892 USA.
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Jacobson
keywords: G protein-coupled receptor; click chemistry; molecular modeling; neuropathic pain; nucleoside