title: Profiling two indole-2-carboxamides for allosteric modulation of the CB1 receptor.
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.
authors.affiliation: Department of Pharmaceutical Sciences, University of Connecticut, Storrs, Connecticut, USA.
authors.forename: Kwang H
authors.initials: KH
authors.lastname: Ahn
authors.forename: Mariam M
authors.initials: MM
authors.lastname: Mahmoud
authors.forename: Sushma
authors.initials: S
authors.lastname: Samala
authors.forename: Dai
authors.initials: D
authors.lastname: Lu
authors.forename: Debra A
authors.initials: DA
authors.lastname: Kendall
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D015151:Immunoblotting; D007211:Indoles / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D008024:Ligands; D010880:Piperidines / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding; D043884:Receptor, Cannabinoid, CB1 / Q000737:chemistry* / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*
chemical_list: C579808:5-chloro-3-ethyl-1-methyl-N-(4-(piperidin-1-yl)phenethyl)-1H-indole-2-carboxamide; C579809:5-chloro-3-pentyl-N-(4-(piperidin-1-yl)phenethyl)-1H-indole-2-carboxamide; D007211:Indoles; D008024:Ligands; D010880:Piperidines; D043884:Receptor, Cannabinoid, CB1