Optimization of Chemical Functionalities of Indole-2-carboxamides To Improve Allosteric Parameters for the Cannabinoid Receptor 1 (CB1)

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• 作者：Leepakshi Khurana ; Hamed I. Ali ; Teresa Olszewska ; Kwang H. Ahn ; Aparna Damaraju ; Debra A. Kendall ; Dai Lu
• 刊名：Journal of Medicinal Chemistry
• 出版年：2014
• 出版时间：April 10, 2014
• 年：2014
• 卷：57
• 期：7
• 页码：3040-3052
• 全文大小：467K
• 年卷期：v.57,no.7(April 10, 2014)
• ISSN：1520-4804

文摘

5-Chloro-3-ethyl-N-(4-(piperidin-1-yl)phenethyl)-1H-indole-2-carboxamide (1; ORG27569) is a prototypical allosteric modulator for the cannabinoid type 1 receptor (CB1). Here, we reveal key structural requirements of indole-2-carboxamides for allosteric modulation of CB1: a critical chain length at the C3-position, an electron withdrawing group at the C5-position, the length of the linker between the amide bond and the phenyl ring B, and the amino substituent on the phenyl ring B. These significantly impact the binding affinity (K_B) and the binding cooperativity (伪). A potent CB1 allosteric modulator 5-chloro-N-(4-(dimethylamino)phenethyl)-3-propyl-1H-indole-2-carboxamide (12d) was identified. It exhibited a K_B of 259.3 nM with a strikingly high binding 伪 of 24.5. We also identified 5-chloro-N-(4-(dimethylamino)phenethyl)-3-hexyl-1H-indole-2-carboxamide (12f) with a K_B of 89.1 nM, which is among the lowest K_B values obtained for any allosteric modulator of CB1. These positive allosteric modulators of orthosteric agonist binding nonetheless antagonized the agonist-induced G-protein coupling to the CB1 receptor, yet induced 尾-arrestin mediated ERK1/2 phosphorylation.