Structure–Activity Relationship Study of Indole-2-carboxamides Identifies a Potent Allosteric Modulator for the Cannabinoid Receptor 1 (CB1)

The cannabinoid CB1 receptor is involved in complex physiological functions. The discovery of CB1 allosteric modulators generates new opportunities for drug discovery targeting the pharmacologically important CB1 receptor. 5-Chloro-3-ethyl-N-(4-(piperidin-1-yl)phenethyl)-1H-indole-2-carboxamide (ORG...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2013-10, Vol.56 (20), p.7965-7975
Main Authors: Mahmoud, Mariam M, Ali, Hamed I, Ahn, Kwang H, Damaraju, Aparna, Samala, Sushma, Pulipati, Venkata K, Kolluru, Srikanth, Kendall, Debra A, Lu, Dai
Format: Article
Language:English
Subjects:
Allosteric Regulation - drug effects
Binding, Competitive
HEK293 Cells
Humans
Indoles - chemical synthesis
Indoles - chemistry
Indoles - pharmacology
Kinetics
Models, Chemical
Molecular Structure
Piperidines - chemistry
Piperidines - pharmacology
Radioligand Assay
Receptor, Cannabinoid, CB1 - genetics
Receptor, Cannabinoid, CB1 - metabolism
Structure-Activity Relationship
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Summary:The cannabinoid CB1 receptor is involved in complex physiological functions. The discovery of CB1 allosteric modulators generates new opportunities for drug discovery targeting the pharmacologically important CB1 receptor. 5-Chloro-3-ethyl-N-(4-(piperidin-1-yl)phenethyl)-1H-indole-2-carboxamide (ORG27569; 1) represents a new class of indole-2-carboxamides that exhibit allostery of CB1. To better understand the SAR, a group of indole-2-carboxamide analogues were synthesized and assessed for allostery of the CB1 receptor. We found that within the structure of indole-2-carboxamides, the presence of the indole ring is preferred for maintaining the modulator’s high binding affinity for the allosteric site but not for generating allostery on the orthosteric site. However, the C3 substituents of the indole-2-carboxamides significantly impact the allostery of the ligand. A robust CB1 allosteric modulator 5-chloro-N-(4-(dimethylamino)phenethyl)-3-pentyl-1H-indole-2-carboxamide (11j) was identified. It showed an equilibrium dissociation constant (K B) of 167.3 nM with a markedly high binding cooperativity factor (α = 16.55) and potent antagonism of agonist-induced GTPγS binding.
ISSN:0022-2623
1520-4804
DOI:10.1021/jm4009828