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 CB1R allosteric modulators using competitive [H-3]-CP55940 and [S-35]-GTP gamma S binding assays.Results: The benzimidazoles 3 and 4 produced significant negative allosteric modulation (NAM) of CP55940 agonism at the mouse CB1R, although are somewhat less potent than the CB1R 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 CB1R, but the modulation on the agonist-induced GTP gamma S binding was maintained.