Profiling two indole‐2‐carboxamides for allosteric modulation of the CB1 receptor

• Published in: Journal of neurochemistry 2013-03, Vol.124 (5), p.584-589
• Main Authors: Ahn, Kwang H., Mahmoud, Mariam M., Samala, Sushma, Lu, Dai, Kendall, Debra A.
• Format: Article
• Language: English
• Subjects: allosteric modulator; Allosteric Regulation - drug effects; biased signaling; CB1; GPCR; G‐protein coupling; HEK293 Cells; Humans; Immunoblotting; Indoles - chemistry; Indoles - metabolism; Indoles - pharmacology; Kinases; ligand binding; Ligands; Neurochemistry; Neurotransmitters; Piperidines - chemistry; Piperidines - metabolism; Piperidines - pharmacology; Protein Binding; Receptor, Cannabinoid, CB1 - chemistry; Receptor, Cannabinoid, CB1 - metabolism; Signal Transduction - drug effects
• ISSN: 0022-3042; 1471-4159
• DOI: 10.1111/jnc.12115

Allosteric modulation of G‐protein coupled receptors (GPCRs) represents a novel approach for fine‐tuning GPCR functions. The cannabinoid CB1 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)‐1H‐indole‐2‐carboxamide (ICAM‐a) and 5‐chloro‐3‐pentyl‐N‐(4‐(piperidin‐1‐yl)phenethyl)‐1H‐indole‐2‐carboxamide (ICAM‐b). Although both ICAM‐a and ICAM‐b enhanced CP55, 940 binding, ICAM‐b exhibited the strongest positive cooperativity thus far demonstrated for enhancing agonist binding to the CB1 receptor. Although it displayed negative modulatory effects on G‐protein coupling to CB1, 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 CB1 ligands that produce biased signaling via CB1. The cannabinoid receptor 1 plays a pivotal role in appetite stimulation, anxiety, and motor control. We report the synthesis and characterization of two indole‐2‐carboxamides as CB1 allosteric modulators: ICAM‐a and ICAM‐b. Although both compounds enhanced agonist binding, ICAM‐b displayed the strongest positive cooperativity and induced G‐protein‐independent β‐arrestin‐mediated ERK signaling. This demonstrates that fine tuning CB1functions are achievable by small‐molecule‐allosteric modulators.