Structural Sweet Spot for A1 Adenosine Receptor Activation by Truncated (N)-Methanocarba Nucleosides: Receptor Docking and Potent Anticonvulsant Activity

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• 作者：Dilip K. Tosh ; Silvia Paoletta ; Francesca Deflorian ; Khai Phan ; Steven M. Moss ; Zhan-Guo Gao ; Xiaohui Jiang ; Kenneth A. Jacobson
• 刊名：Journal of Medicinal Chemistry
• 出版年：2012
• 出版时间：September 27, 2012
• 年：2012
• 卷：55
• 期：18
• 页码：8075-8090
• 全文大小：640K
• 年卷期：v.55,no.18(September 27, 2012)
• ISSN：1520-4804

文摘

A₁ adenosine receptor (AR) agonists display antiischemic and antiepileptic neuroprotective activity, but peripheral cardiovascular side effects impeded their development. SAR study of N⁶-cycloalkylmethyl 4鈥?truncated (N)-methanocarba-adenosines identified 10 (MRS5474, N⁶-dicyclopropylmethyl, K_i = 47.9 nM) as a moderately A₁AR-selective full agonist. Two stereochemically defined N⁶-methynyl group substituents displayed narrow SAR; groups larger than cyclobutyl greatly reduced AR affinity, and those larger or smaller than cyclopropyl reduced A₁AR selectivity. Nucleoside docking to A₁AR homology model characterized distinct hydrophobic cyclopropyl subpockets, the larger 鈥淎鈥?forming contacts with Thr270 (7.35), Tyr271 (7.36), Ile274 (7.39), and carbon chains of glutamates (EL2) and the smaller subpocket 鈥淏鈥?forming contacts between TM6 and TM7. 10 suppressed minimal clonic seizures (6 Hz mouse model) without typical rotarod impairment of A₁AR agonists. Truncated nucleosides, an appealing preclinical approach, have more druglike physicochemical properties than other A₁AR agonists. Thus, we identified highly restricted regions for substitution around N⁶ suitable for an A₁AR agonist with anticonvulsant activity.