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

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.
(© 2018 The British Pharmacological Society.)