Allosteric and orthosteric pharmacology of cannabidiol and cannabidiol‐dimethylheptyl at the type 1 and type 2 cannabinoid receptors

Abstract

Background and Purpose: We sought to understand why (−)‐cannabidiol (CBD) and (−)‐cannabidiol‐dimethylheptyl (CBD‐DMH) exhibit distinct pharmacology, despite near identical structures. Experimental Approach: HEK293A cells expressing either human type 1 cannabinoid (CB 1) receptors or CB 2 receptors were treated with CBD or CBD‐DMH with or without the CB 1 and CB 2 receptor agonist CP55,940, CB 1 receptor allosteric modulator Org27569 or CB 2 receptor inverse agonist SR144528. Ligand binding, cAMP levels and βarrestin1 recruitment were measured. CBD and CBD‐DMH binding was simulated with models of human CB 1 or CB 2 receptors, based on the recently published crystal structures of agonist‐bound (5XRA) or antagonist‐bound (5TGZ) human CB 1 receptors. Key Results: At CB 1 receptors, CBD was a negative allosteric modulator (NAM), and CBD‐DMH was a mixed agonist/positive allosteric modulator. CBD and Org27569 shared multiple interacting residues in the antagonist‐bound model of CB 1 receptors (5TGZ) but shared a binding site with CP55,940 in the agonist‐bound model of CB 1 receptors (5XRA). The binding site for CBD‐DMH in the CB 1 receptor models overlapped with CP55,940 and Org27569. At CB 2 receptors, CBD was a partial agonist, and CBD‐DMH was a positive allosteric modulator of cAMP modulation but a NAM of βarrestin1 recruitment. CBD, CP55,940 and SR144528 shared a binding site in the CB 2 receptor models that was separate from CBD‐DMH. Conclusion and Implications: The pharmacological activity of CBD and CBD‐DMH in HEK293A cells and their modelled binding sites at CB 1 and CB 2 receptors may explain their in vivo effects and illuminates the difficulties associated with the development of allosteric modulators for CB 1 and CB 2 receptors. Linked Articles: This article is part of a themed section on 8 th European Workshop on Cannabinoid Research. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.10/issuetoc