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 [³H]-CP55940 and [³⁵S]-GTPγS 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 GTPγS binding was maintained.