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

Leepakshi Khurana; Hamed I. Ali; Teresa Olszewska; Kwang H. Ahn; Aparna Damaraju; Debra A. Kendall; Dai Lu

doi:10.1021/jm5000112

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

Abstract

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 (KB) and the binding cooperativity (α). A potent CB1 allosteric modulator 5-chloro-N-(4-(dimethylamino)phenethyl)-3-propyl-1H-indole-2-carboxamide (12d) was identified. It exhibited a KB of 259.3 nM with a strikingly high binding α of 24.5. We also identified 5-chloro-N-(4-(dimethylamino)phenethyl)-3-hexyl-1H-indole-2-carboxamide (12f) with a KB of 89.1 nM, which is among the lowest KB 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 β-arrestin mediated ERK1/2 phosphorylation.

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Authors (7)

Leepakshi Khurana
- . .
Hamed I. Ali
- . .
Teresa Olszewska dr hab. inż.
Kwang H. Ahn
- . .
Aparna Damaraju
- . .
Debra A. Kendall
- . .
Dai Lu
- . .

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DOI:: Digital Object Identifier (open in new tab) 10.1021/jm5000112
License: Copyright (2014 American Chemical Society)

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Category:: Articles
Type:: artykuł w czasopiśmie wyróżnionym w JCR
Published in:: JOURNAL OF MEDICINAL CHEMISTRY no. 57, edition 7, pages 3040 - 3052,
ISSN: 0022-2623
Language:: English
Publication year:: 2014
Bibliographic description:: Khurana L., Ali H., Olszewska T., Ahn K., Damaraju A., Kendall D., Lu D.: Optimization of Chemical Functionalities of Indole-2-carboxamides To Improve Allosteric Parameters for the Cannabinoid Receptor 1 (CB1)// JOURNAL OF MEDICINAL CHEMISTRY. -Vol. 57, iss. 7 (2014), s.3040-3052
DOI:: Digital Object Identifier (open in new tab) 10.1021/jm5000112
Verified by:: Gdańsk University of Technology