Rigidified A3 Adenosine Receptor Agonists: 1-Deazaadenine Modification Maintains High in Vivo Efficacy

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• 作者：Dilip K. Tosh ; Steven Crane ; Zhoumou Chen ; Silvia Paoletta ; Zhan-Guo Gao ; Elizabeth Gizewski ; John A. Auchampach ; Daniela Salvemini ; Kenneth A. Jacobson
• 刊名：ACS Medicinal Chemistry Letters
• 出版年：2015
• 出版时间：July 9, 2015
• 年：2015
• 卷：6
• 期：7
• 页码：804-808
• 全文大小：371K
• ISSN：1948-5875

文摘

Substitution of rigidified A₃ adenosine receptor (AR) agonists with a 2-((5-chlorothiophen-2-yl)ethynyl) or a 2-(4-(5-chlorothiophen-2-yl)-1H-1,2,3-triazol-1-yl) group provides prolonged protection in a model of chronic neuropathic pain. These agonists contain a bicyclo[3.1.0]hexane ((N)-methanocarba) ring system in place of ribose, which adopts a receptor-preferred conformation. N⁶-Small alkyl derivatives were newly optimized for A₃AR affinity and the effects of a 1-deaza-adenine modification probed. 1-Deaza-N⁶-ethyl alkyne 20 (MRS7144, K_i 1.7 nM) and 1-aza N⁶-propyl alkyne 12 (MRS7154, K_i 1.1 nM) were highly efficacious in vivo. Thus, the presence of N1 is not required for nanomolar binding affinity or potent, long-lasting functional activity. Docking of 1-deaza compounds to a receptor homology model confirmed a similar binding mode as previously reported 1-aza derivatives. This is the first demonstration in nonribose adenosine analogues that the 1-deaza modification can maintain high A₃AR affinity, selectivity, and efficacy.