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
06/25/2013Pubmed ID
23789857Pubmed Central ID
PMC3858399DOI
10.1021/jm4007966Scopus ID
2-s2.0-84880866056 32 CitationsAbstract
(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 KAAuthor
John A. Auchampach PhD Professor in the Pharmacology and Toxicology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Adenosine A3 Receptor AgonistsAnimals
CHO Cells
Chronic Pain
Cricetinae
Cricetulus
Drug Design
Male
Mice
Models, Molecular
Molecular Docking Simulation
Neuralgia
Nucleosides
Receptor, Adenosine A3
Structure-Activity Relationship
