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Rational design of sulfonated A3 adenosine receptor-selective nucleosides as pharmacological tools to study chronic neuropathic pain.

Thursday, November 07, 2013 — Poster Session II

12:00 p.m. – 2:00 p.m.

FAES Academic Center (Upper-Level Terrace)




  • S. Paoletta
  • D.K. Tosh
  • A. Finley
  • E.T. Gizewski
  • S.M. Moss
  • Z.G. Gao
  • J.A. Auchampach
  • D. Salvemini
  • K.A. Jacobson


Agonists of the Gi-coupled A3 adenosine receptor (AR) have been recently shown to be efficacious in mouse models of chronic pain, reversing mechanically- and chemotherapy-induced allodynia and showing potential as a new, targeted therapy. In this study, (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 N6-p-sulfo-phenylethyl 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. N6-3-chlorobenzyl-2-(3-sulfophenylethynyl) derivative (MRS5481) bound selectively to h/m A3ARs (Ki hA3AR 1.9 nM) as agonist, while corresponding p-sulfo isomer (MRS5701) displayed mixed A1/A3AR agonism. Both nucleosides administered i.p. reduced mouse chronic neuropathic pain that was ascribed to either A3 or A1/A3ARs using A3AR genetic deletion. Thus, rational design methods, based on A3AR homology models, successfully predicted sites for sulfonate incorporation on (N)-methanocarba nucleosides developing compounds with species-independent A3 affinity, useful in delineating adenosine’s CNS vs. peripheral actions.

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