October 9 - 12, 2012
Building 10 & Natcher Conference Center
- General Schedule of Events
- Opening Plenary Session
- Concurrent Symposia Sessions
- Poster Sessions
- National Graduate Student Research Conference
- FARE Award Ceremony
- Special Exhibits on Resources for Intramural Research
- TSA Research Festival Exhibit Show
- Clinical Center Tours
- Research Festival Committees
- Past Research Festivals
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) |
NIDDK |
CHEMCELL-20 |
Authors
- S. Paoletta
- D.K. Tosh
- A. Finley
- E.T. Gizewski
- S.M. Moss
- Z.G. Gao
- J.A. Auchampach
- D. Salvemini
- K.A. Jacobson
Abstract
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.
