title: In vivo phenotypic screening for treating chronic neuropathic pain: modification of C2-arylethynyl group of conformationally constrained A3 adenosine receptor agonists.
abstract: (N)-Methanocarba adenosine 5'-methyluronamides containing 2-arylethynyl groups were synthesized as A3 adenosine receptor (AR) agonists and screened in vivo (po) for reduction of neuropathic pain. A small N(6)-methyl group maintained binding affinity, with human > mouse A3AR and MW < 500 and other favorable physicochemical properties. Emax (maximal efficacy in a mouse chronic constriction injury pain model) of previously characterized A3AR agonist, 2-(3,4-difluorophenylethynyl)-N(6)-(3-chlorobenzyl) derivative 6a, MRS5698, was surpassed. More efficacious analogues (in vivo) contained the following C2-arylethynyl groups: pyrazin-2-yl 23 (binding Ki, hA3AR, nM 1.8), fur-2-yl 27 (0.6), thien-2-yl 32 (0.6) and its 5-chloro 33, MRS5980 (0.7) and 5-bromo 34 (0.4) equivalents, and physiologically unstable ferrocene 36, MRS5979 (2.7). 33 and 36 displayed particularly long in vivo duration (>3 h). Selected analogues were docked to an A3AR homology model to explore the environment of receptor-bound C2 and N(6) groups. Various analogues bound with μM affinity at off-target biogenic amine (M2, 5HT2A, β3, 5HT2B, 5HT2C, and α2C) or other receptors. Thus, we have expanded the structural range of orally active A3AR agonists for chronic pain treatment.
authors.affiliation: Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health , Building 8A, Room B1A-19, Bethesda, Maryland 20892-0810, United States.
authors.forename: Dilip K
authors.initials: DK
authors.lastname: Tosh
authors.forename: Amanda
authors.initials: A
authors.lastname: Finley
authors.forename: Silvia
authors.initials: S
authors.lastname: Paoletta
authors.forename: Steven M
authors.initials: SM
authors.lastname: Moss
authors.forename: Zhan-Guo
authors.initials: ZG
authors.lastname: Gao
authors.forename: Elizabeth T
authors.initials: ET
authors.lastname: Gizewski
authors.forename: John A
authors.initials: JA
authors.lastname: Auchampach
authors.forename: Daniela
authors.initials: D
authors.lastname: Salvemini
authors.forename: Kenneth A
authors.initials: KA
authors.lastname: Jacobson
mesh_terms: D058909:Adenosine A3 Receptor Agonists / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D016466:CHO Cells; D003412:Cricetulus; D006801:Humans; D051379:Mice; D009437:Neuralgia / Q000188:drug therapy*; D013329:Structure-Activity Relationship
chemical_list: D058909:Adenosine A3 Receptor Agonists