title: Rational design of sulfonated A3 adenosine receptor-selective nucleosides as pharmacological tools to study chronic neuropathic pain.
abstract: (N)-Methanocarba(bicyclo[3.1.0]hexane)adenosine derivatives were probed for sites of charged sulfonate substitution, which precludes diffusion across biological membranes, e.g., blood-brain barrier. Molecular modeling predicted that sulfonate groups on C2-phenylethynyl substituents would provide high affinity at both mouse (m) and human (h) A3 adenosine receptors (ARs), while a N(6)-p-sulfophenylethyl substituent would determine higher hA3AR vs mA3AR affinity. These modeling predictions, based on steric fitting of the binding cavity and crucial interactions with key residues, were confirmed by binding/efficacy studies of synthesized sulfonates. N(6)-3-Chlorobenzyl-2-(3-sulfophenylethynyl) derivative 7 (MRS5841) bound selectively to h/m A3ARs (Ki(hA3AR) = 1.9 nM) as agonist, while corresponding p-sulfo isomer 6 (MRS5701) displayed mixed A1/A3AR agonism. Both nucleosides administered ip reduced mouse chronic neuropathic pain that was ascribed to either A3AR or A1/A3AR using A3AR genetic deletion. Thus, rational design methods based on A3AR homology models successfully predicted sites for sulfonate incorporation, for delineating adenosine's CNS vs peripheral actions.
authors.affiliation: Molecular Recognition Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health , Bethesda, Maryland 20892-0810, United States.
authors.forename: Silvia
authors.initials: S
authors.lastname: Paoletta
authors.forename: Dilip K
authors.initials: DK
authors.lastname: Tosh
authors.forename: Amanda
authors.initials: A
authors.lastname: Finley
authors.forename: Elizabeth T
authors.initials: ET
authors.lastname: Gizewski
authors.forename: Steven M
authors.initials: SM
authors.lastname: Moss
authors.forename: Zhan-Guo
authors.initials: ZG
authors.lastname: Gao
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* / Q000378:metabolism / Q000627:therapeutic use; D000818:Animals; D016466:CHO Cells; D059350:Chronic Pain / Q000188:drug therapy*; D006224:Cricetinae; D003412:Cricetulus; D015195:Drug Design; D008297:Male; D051379:Mice; D008958:Models, Molecular; D062105:Molecular Docking Simulation; D009437:Neuralgia / Q000188:drug therapy*; D009705:Nucleosides / Q000138:chemical synthesis* / Q000378:metabolism / Q000627:therapeutic use; D043684:Receptor, Adenosine A3 / Q000737:chemistry; D013329:Structure-Activity Relationship
chemical_list: D058909:Adenosine A3 Receptor Agonists; D009705:Nucleosides; D043684:Receptor, Adenosine A3