Profiling two indole‐2‐carboxamides for allosteric modulation of the CB1 receptor |
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Authors: | Kwang H Ahn Mariam M Mahmoud Sushma Samala Dai Lu Debra A Kendall |
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Institution: | 1. Department of Pharmaceutical Sciences, University of Connecticut, , Storrs, Connecticut, USA;2. Department of Molecular and Cell Biology, University of Connecticut, , Storrs, Connecticut, USA;3. Department of Pharmaceutical Sciences, Irma Lerma Rangel College of Pharmacy, Texas A&M Health Science Center, , Kingsville, Texas, USA |
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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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Keywords: | allosteric modulator biased signaling CB1 G‐protein coupling
GPCR
ligand binding |
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