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

Laura Hernandez-Folgado*, Lesley A. Stevenson, Paula Morales, María Gómez-Cañas, María Ruth Pazos, Maria Grazia Cascio, Nadine Jagerovic, José Elguero, Roger Pertwee, Pilar Goya

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

2 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)196-201
Number of pages6
JournalCannabis and Cannabinoid Research
Issue number1
Early online date1 Aug 2016
Publication statusPublished - Dec 2016


  • allosteric modulators
  • benzimidazole
  • CB receptor
  • ORG27569


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