Evidence that the plant cannabinoid cannabigerol is a highly potent α _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 Δ⁹‐tetrahydrocannabinol, cannabidiol and Δ⁹‐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]GTPγS 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 α₂‐adrenoceptor agonist (EC₅₀= 0.2 nM) and antagonized the 5‐HT_1A receptor agonist, R‐(+)‐8‐hydroxy‐2‐(di‐n‐propylamino)tetralin (apparent K_B= 51.9 nM). At 10 µM, 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 α₂‐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 α₂‐adrenoceptors, bind to cannabinoid CB₁ and CB₂ receptors and block CB₁ and 5‐HT_1A receptors. It will now be important to investigate why cannabigerol produced signs of agonism more potently in the [³⁵S]GTPγS binding assay than in the vas deferens and also whether it can inhibit noradrenaline uptake in this isolated tissue and in the brain.