Mariam M Mahmoud, Hamed I Ali, Kwang H Ahn, Aparna Damaraju, Sushma Samala, Venkata K Pulipati, Srikanth Kolluru, Debra A Kendall, Dai Lu
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 (KB) of 167.3 nM with a markedly high binding cooperativity factor (α = 16.55) and potent antagonism of agonist-induced GTPγS binding.
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Allosteric Regulation
Binding, Competitive
HEK293 Cells
Humans
Indoles
Kinetics
Models, Chemical
Molecular Structure
Piperidines
Radioligand Assay
Receptor, Cannabinoid, CB1
Structure-Activity Relationship
5-chloro-3-ethyl-1H-indole-2-carboxylic acid (2-(4-piperidin-1-yl-phenyl)ethyl)amide
5-chloro-N-(4-(dimethylamino)phenethyl)-3-pentyl-1H-indole-2-carboxamide
Indoles
Piperidines
Receptor, Cannabinoid, CB1
