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Rational design of sulfonated A3 adenosine receptor-selective nucleosides as pharmacological tools to study chronic neuropathic pain. J Med Chem 2013 Jul 25;56(14):5949-63

Date

06/25/2013

Pubmed ID

23789857

Pubmed Central ID

PMC3858399

DOI

10.1021/jm4007966

Scopus ID

2-s2.0-84880866056   32 Citations

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.

Author List

Paoletta S, Tosh DK, Finley A, Gizewski ET, Moss SM, Gao ZG, Auchampach JA, Salvemini D, Jacobson KA

Author

John A. Auchampach PhD Professor in the Pharmacology and Toxicology department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Adenosine A3 Receptor Agonists
Animals
CHO Cells
Chronic Pain
Cricetinae
Cricetulus
Drug Design
Male
Mice
Models, Molecular
Molecular Docking Simulation
Neuralgia
Nucleosides
Receptor, Adenosine A3
Structure-Activity Relationship
jenkins-FCD Prod-486 e3098984f26de787f5ecab75090d0a28e7f4f7c0