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Profiling two indole‐2‐carboxamides for allosteric modulation of the CB 1 receptor
Author(s) -
Ahn Kwang H.,
Mahmoud Mariam M.,
Samala Sushma,
Lu Dai,
Kendall Debra A.
Publication year - 2013
Publication title -
journal of neurochemistry
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.75
H-Index - 229
eISSN - 1471-4159
pISSN - 0022-3042
DOI - 10.1111/jnc.12115
Subject(s) - g protein coupled receptor , allosteric regulation , allosteric modulator , receptor , cannabinoid receptor , chemistry , agonist , functional selectivity , pharmacology , indole test , cannabinoid , biochemistry , biology
Allosteric modulation of G‐protein coupled receptors ( GPCR s) represents a novel approach for fine‐tuning GPCR functions. The cannabinoid CB 1 receptor, a GPCR associated with the CNS , has been implicated in the treatment of drug addiction, pain, and appetite disorders. We report here the synthesis and pharmacological characterization of two indole‐2‐carboxamides:5‐chloro‐3‐ethyl‐1‐methyl‐N‐(4‐(piperidin‐1‐yl)phenethyl)‐1 H ‐indole‐2‐carboxamide ( ICAM ‐a) and 5‐chloro‐3‐pentyl‐N‐(4‐(piperidin‐1‐yl)phenethyl)‐1 H ‐indole‐2‐carboxamide ( ICAM ‐b). Although both ICAM ‐a and ICAM ‐b enhanced CP 55, 940 binding, ICAM ‐b exhibited the strongest positive cooperativity thus far demonstrated for enhancing agonist binding to the CB 1 receptor. Although it displayed negative modulatory effects on G‐protein coupling to CB 1, ICAM ‐b induced β‐arrestin‐mediated downstream activation of extracellular signal‐regulated kinase ( ERK ) signaling. These results indicate that this compound represents a novel class of CB 1 ligands that produce biased signaling via CB 1.