Cannabidiol is a negative allosteric modulator of the cannabinoid CB1 receptor.

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Laprairie RB, Bagher AM, Kelly ME, Denovan-Wright EM

Cannabidiol is a negative allosteric modulator of the cannabinoid CB1 receptor.

Br J Pharmacol. 2015 Oct;172(20):4790-805. doi: 10.1111/bph.13250. Epub 2015 Oct 13.

PubMed ID

26218440 [ View in PubMed

]

Abstract

BACKGROUND AND PURPOSE: Cannabidiol has been reported to act as an antagonist at cannabinoid CB1 receptors. We hypothesized that cannabidiol would inhibit cannabinoid agonist activity through negative allosteric modulation of CB1 receptors. EXPERIMENTAL APPROACH: Internalization of CB1 receptors, arrestin2 recruitment, and PLCbeta3 and ERK1/2 phosphorylation, were quantified in HEK 293A cells heterologously expressing CB1 receptors and in the STHdh(Q7/Q7) cell model of striatal neurons endogenously expressing CB1 receptors. Cells were treated with 2-arachidonylglycerol or Delta(9)-tetrahydrocannabinol alone and in combination with different concentrations of cannabidiol. KEY RESULTS: Cannabidiol reduced the efficacy and potency of 2-arachidonylglycerol and Delta(9)-tetrahydrocannabinol on PLCbeta3- and ERK1/2-dependent signalling in cells heterologously (HEK 293A) or endogenously (STHdh(Q7/Q7)) expressing CB1 receptors. By reducing arrestin2 recruitment to CB1 receptors, cannabidiol treatment prevented internalization of these receptors. The allosteric activity of cannabidiol depended upon polar residues being present at positions 98 and 107 in the extracellular amino terminus of the CB1 receptor. CONCLUSIONS AND IMPLICATIONS: Cannabidiol behaved as a non-competitive negative allosteric modulator of CB1 receptors. Allosteric modulation, in conjunction with effects not mediated by CB1 receptors, may explain the in vivo effects of cannabidiol. Allosteric modulators of CB1 receptors have the potential to treat CNS and peripheral disorders while avoiding the adverse effects associated with orthosteric agonism or antagonism of these receptors.

DrugBank Data that Cites this Article

Drugs

Cannabidiol

Medical Cannabis

Nabiximols

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Cannabidiol	Cannabinoid receptor 1	Protein	Humans	Yes	Antagonist Modulator	Details
Medical Cannabis	Cannabinoid receptor 1	Protein	Humans	Yes	Negative modulator	Details
Nabiximols	Cannabinoid receptor 1	Protein	Humans	Yes	Not Available	Details
Nabiximols	G-protein coupled receptor 12	Protein	Humans	Unknown	Inverse agonist	Details