Evidence that the plant cannabinoid cannabigerol is a highly potent a 2 - adrenoceptor agonist and moderately potent 5 HT 1 A receptor antagonistbph

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 D9-tetrahydrocannabinol, cannabidiol and D9-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 [35S]GTPgS 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 [3H]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 a2-adrenoceptor agonist (EC50 = 0.2 nM) and antagonized the 5-HT1A receptor agonist, R-(+)-8-hydroxy-2-(di-n-propylamino)tetralin (apparent KB = 51.9 nM). At 10 mM, 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 a2-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 a2-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 [35S]GTPgS 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