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Exploring the Benzimidazole Ring as a Substitution for Indole in Cannabinoid Allosteric Modulators

AuthorsHernández-Folgado, Laura ; Stevenson, Lesley A.; Morales, Paula ; Gómez-Cañas, María; Pazos, Ruth; Cascio, Grazia; Jagerovic, Nadine ; Elguero, José ; Pertwee, Roger; Goya, Pilar
KeywordsAllosteric modulators
CB1 receptor
Issue Date2016
PublisherMary Ann Liebert
CitationCannabis and Cannabinoid Research 1: 196-200 (2016)
AbstractIntroduction and Objectives: The traditional approach to target a particular receptor is to design compounds that bind to the same site as the endogenous ligand, the so-called ‘‘orthosteric site.’’ However, recently the search has shifted to ligands that can interact with a different region of the receptor protein, the ‘‘allosteric site,’’ since this approach offers potential pharmacological and therapeutic advantages. The aim of our work was to explore the benzimidazole heterocycle as a novel scaffold for cannabinoid allosterism. Materials and Methods: We synthesized a series of novel benzimidazole-2-carboxamides, analogues of ORG27569, and performed their pharmacological characterization as CB 1 R allosteric modulators using compe- titive [ 3 H]-CP55940 and [ 35 S]-GTP c S binding assays. Results: The benzimidazoles 3 and 4 produced significant negative allosteric modulation (NAM) of CP55940 agonism at the mouse CB 1 R, although are somewhat less potent than the CB 1 R allosteric cannabinoid ORG27569. Conclusions: Replacing the indole ring with a benzimidazole ring within the structure of ORG27569 abolished the binding of the resultant ligands to CB 1 R, but the modulation on the agonist-induced GTP c S binding was maintained
Publisher version (URL)http://dx.doi.org/10.1089/can.2016.0003
Identifiersdoi: 10.1089/can.2016.0003
issn: 2378-8763
Appears in Collections:(IQM) Artículos
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