Rational Design of Sulfonated A3 Adenosine Receptor-Selective Nucleosides as Pharmacological Tools To Study Chronic Neuropathic Pain

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• 作者：Silvia Paoletta ; Dilip K. Tosh ; Amanda Finley ; Elizabeth T. Gizewski ; Steven M. Moss ; Zhan-Guo Gao ; John A. Auchampach ; Daniela Salvemini ; Kenneth A. Jacobson
• 刊名：Journal of Medicinal Chemistry
• 出版年：2013
• 出版时间：July 25, 2013
• 年：2013
• 卷：56
• 期：14
• 页码：5949-5963
• 全文大小：884K
• 年卷期：v.56,no.14(July 25, 2013)
• ISSN：1520-4804

文摘

(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鈥揵rain 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-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. N⁶-3-Chlorobenzyl-2-(3-sulfophenylethynyl) derivative 7 (MRS5841) bound selectively to h/m A₃ARs (K_i(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鈥檚 CNS vs peripheral actions.