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

Introduction 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 maintainedThe authors gratefully acknowledge research support from Spanish Grant SAF2012-400075-C02-02 and CAM S2010/BMD-2308. P.M. is recipient of a fellowship JAE-Pre-2010-01119 from ‘‘Junta para la Ampliación de Estudios’’ that is co-financed by FSE.Peer Reviewe