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

Authors


Address correspondence and reprint requests to Debra A. Kendall, Department of Pharmaceutical Sciences, 69 N. Eagleville Road, Storrs, CT 06269-3092, USA. E-mail: debra.kendall@uconn.edu or Dai Lu, Department of Pharmaceutical Sciences, Irma Lerma Rangel College of Pharmacy, 1010 West Avenue B, Kingsville, Texas 78363, USA. E-mail: dlu@tamhsc.edu

Abstract

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.

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