Evidence that the plant cannabinoid cannabigerol is a highly potent α₂-adrenoceptor agonist and moderately potent 5HT_1A receptor antagonist

Background and purpose: Cannabis is the source of at least seventy phytocannabinoids. The pharmacology of most of these has been little investigated, three notable exceptions being Delta(9)-tetrahydrocannabinol, cannabidiol and Delta(9)-tetrahydrocannabivarin. This investigation addressed the question of whether the little-studied phytocannabinoid, cannabigerol, can activate or block any G protein-coupled receptor.

Experimental approach: The [S-35]GTP gamma S binding assay, performed with mouse brain membranes, was used to test the ability of cannabigerol to produce G protein-coupled receptor activation or blockade. Its ability to displace [H-3]CP55940 from mouse CB1 and human CB2 cannabinoid receptors and to inhibit electrically evoked contractions of the mouse isolated vas deferens was also investigated.

Key results: In the brain membrane experiments, cannabigerol behaved as a potent alpha(2)-adrenoceptor agonist (EC50 = 0.2 nM) and antagonized the 5-HT1A receptor agonist, R-(+)-8-hydroxy-2-(di-n-propylamino)tetralin (apparent K-B = 51.9 nM). At 10 mu M, it also behaved as a CB1 receptor competitive antagonist. Additionally, cannabigerol inhibited evoked contractions of the vas deferens in a manner that appeared to be alpha(2)-adrenoceptor-mediated (EC50 = 72.8 nM) and displayed significant affinity for mouse CB1 and human CB2 receptors.

Conclusions and implications: This investigation has provided the first evidence that cannabigerol can activate alpha(2)-adrenoceptors, bind to cannabinoid CB1 and CB2 receptors and block CB1 and 5-HT1A receptors. It will now be important to investigate why cannabigerol produced signs of agonism more potently in the [S-35]GTP gamma S binding assay than in the vas deferens and also whether it can inhibit noradrenaline uptake in this isolated tissue and in the brain. British Journal of Pharmacology (2010) 159, 129-141; doi:10.1111/j.1476-5381.2009.00515.x; published online 4 December 2009