Allosteric and orthosteric pharmacology of cannabidiol and cannabidiol-dimethylheptyl at the type 1 and type 2 cannabinoid receptors.
Br J Pharmacol. 2018 Jul 07;:
Authors: Tham M, Yilmaz O, Alaverdashvili M, Kelly MEM, Denovan-Wright EM, Laprairie RB
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 receptor (CB1R) or type 2 cannabinoid receptor (CB2R) were treated with CBD or CBD-DMH with or without the CB1R and CB2R agonist CP55,940, the CB1R allosteric modulator Org27569 or the CB2R inverse agonist SR144528. Ligand binding, cAMP levels, and βarrestin1 recruitment were measured. CBD and CBD-DMH binding was simulated with models of human CB1R or CB2R, based on the recently published crystal structures of agonist-bound (5XRA) or antagonist-bound (5TGZ) human CB1R.
KEY RESULTS: At CB1R, 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 CB1R (5TGZ), but shared a binding site with CP55,940 in the agonist-bound model of CB1R (5XRA). The binding site for CBD-DMH in the CB1R models overlapped with CP55,940 and Org27569. At CB2R, 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 CB2R 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 CB1R and CB2R may explain their in vivo effects and illuminates the difficulties associated with the development of allosteric modulators for CB1R and CB2R.
PMID: 29981240 [PubMed – as supplied by publisher]
Source: Estudios sobre Cannabidiol (CBD)