Purine (N)-Methanocarba Nucleoside Derivatives Lacking an Exocyclic Amine as Selective A3 Adenosine Receptor Agonists

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• 作者：Dilip K. Tosh ; Antonella Ciancetta ; Eugene Warnick ; Robert O’Connor ; Zhoumou Chen ; Elizabeth Gizewski ; Steven Crane ; Zhan-Guo Gao ; John A. Auchampach ; Daniela Salvemini ; Kenneth A. Jacobson
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：April 14, 2016
• 年：2016
• 卷：59
• 期：7
• 页码：3249-3263
• 全文大小：789K
• 年卷期：0
• ISSN：1520-4804

文摘

Purine (N)-methanocarba-5′-N-alkyluronamidoriboside A₃ adenosine receptor (A₃AR) agonists lacking an exocyclic amine resulted from an unexpected reaction during a Sonogashira coupling and subsequent aminolysis. Because the initial C6-Me and C6-styryl derivatives had unexpectedly high A₃AR affinity, other rigid nucleoside analogues lacking an exocyclic amine were prepared. Of these, the C6-Me-(2-phenylethynyl) and C2-(5-chlorothienylethynyl) analogues were particularly potent, with human A₃AR K_i values of 6 and 42 nM, respectively. Additionally, the C2-(5-chlorothienyl)-6-H analogue was potent and selective at A₃AR (MRS7220, K_i 60 nM) and also completely reversed mouse sciatic nerve mechanoallodynia (in vivo, 3 μmol/kg, po). The lack of a C6 H-bond donor while maintaining A₃AR affinity and efficacy could be rationalized by homology modeling and docking of these hypermodified nucleosides. The modeling suggests that a suitable combination of stabilizing features can partially compensate for the lack of an exocyclic amine, an otherwise important contributor to recognition in the A₃AR binding site.