Structure-Based Scaffold Repurposing for G Protein-Coupled Receptors: Transformation of Adenosine Derivatives into 5HT2B/5HT2C Serotonin Receptor Antagonists

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• 作者：Dilip K. Tosh ; Antonella Ciancetta ; Eugene Warnick ; Steven Crane ; Zhan-Guo Gao ; Kenneth A. Jacobson
• 刊名：Journal of Medicinal Chemistry
• 出版年：2016
• 出版时间：December 22, 2016
• 年：2016
• 卷：59
• 期：24
• 页码：11006-11026
• 全文大小：1242K
• ISSN：1520-4804

文摘

Adenosine derivatives developed to activate adenosine receptors (ARs) revealed micromolar activity at serotonin 5HT_2B and 5HT_2C receptors (5HTRs). We explored the structure–activity relationship at 5HT₂Rs and modeled receptor interactions in order to optimize affinity and simultaneously reduce AR affinity. Depending on N⁶ substitution, small 5′-alkylamide modification maintained 5HT_2BR affinity, which was enhanced upon ribose substitution with rigid bicyclo[3.1.0]hexane (North (N)-methanocarba), e.g., N⁶-dicyclopropylmethyl 4′-CH₂OH derivative 14 (K_i 11 nM). 5′-Methylamide 23 was 170-fold selective as antagonist for 5HT_2BR vs 5HT_2CR. 5′-Methyl 25 and ethyl 26 esters potently antagonized 5HT₂Rs with moderate selectivity in comparison to ARs; related 6-N,N-dimethylamino analogue 30 was 5HT₂R-selective. 5′ position flexibility of substitution was indicated in 5HT_2BR docking. Both 5′-ester and 5′-amide derivatives displayed in vivo t_1/2 of 3–4 h. Thus, we used G protein-coupled receptor modeling to repurpose nucleoside scaffolds in favor of binding at nonpurine receptors as novel 5HT₂R antagonists, with potential for cardioprotection, liver protection, or central nervous system activity.