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

and Objectives:\udThe traditional approach to target a particular receptor is to design compounds\udthat bind to the same site as the endogenous ligand, the so-called ‘‘orthosteric site.’’ However, recently the search\udhas shifted to ligands that can interact with a different region of the receptor protein, the ‘‘allosteric site,’’ since\udthis approach offers potential pharmacological and therapeutic advantages. The aim of our work was to explore\udthe benzimidazole heterocycle as a novel scaffold for cannabinoid allosterism.\udMaterials and Methods:\udWe synthesized a series of novel benzimidazole-2-carboxamides, analogues of\udORG27569, and performed their pharmacological characterization as CB\ud1\udR allosteric modulators using compe-\udtitive [\ud3\udH]-CP55940 and [\ud35\udS]-GTP\udc\udS binding assays.\udResults:\udThe benzimidazoles\ud3\udand\ud4\udproduced significant negative allosteric modulation (NAM) of CP55940\udagonism at the mouse CB\ud1\udR, although are somewhat less potent than the CB\ud1\udR allosteric cannabinoid ORG27569.\udConclusions:\udReplacing the indole ring with a benzimidazole ring within the structure of ORG27569 abolished\udthe binding of the resultant ligands to CB\ud1\udR, but the modulation on the agonist-induced GTP\udc\udS binding was\udmaintainedThe authors gratefully acknowledge research support\udfrom Spanish Grant SAF2012-400075-C02-02 and\udCAM S2010/BMD-2308. P.M. is recipient of a fellowship\udJAE-Pre-2010-01119 from ‘‘Junta para la Ampliación de Estudios’’ that is co-financed by FSE.Peer Reviewe