Pharmacology of Minor Cannabinoids at the Cannabinoid CB1 Receptor: Isomer- and Ligand-Dependent Antagonism by Tetrahydrocannabivarin

(1) Background: In addition to the major phytocannabinoids, trans-Δ⁹-tetrahydrocannabinol (Δ⁹-THC) and cannabidiol (CBD), the cannabis plant (Cannabis sativa L.) synthesizes over 120 additional cannabinoids that are known as minor cannabinoids. These minor cannabinoids have been proposed to act as agonists and antagonists at numerous targets including cannabinoid type 1 (CB₁) and type 2 (CB₂) receptors, transient receptor potential (TRP) channels and others. The goal of the present study was to determine the agonist effects of the minor cannabinoids: cannabinol (CBN), cannabigerol (CBG), cannabichromene (CBC), cannabitriol (CBT) and cannabidivarin (CBDV) at the CB₁ receptor. In addition, the CB₁ receptor antagonist effects of Δ⁹-tetrahydrocannabivarin (Δ⁹-THCV) were compared with its isomer Δ⁸-tetrahydrocannabivarin (Δ⁸-THCV). (2) Methods: CB₁ receptor activity was monitored by measuring cannabinoid activation of G protein-gated inward rectifier K⁺ (GIRK) channels in AtT20 pituitary cells using a membrane potential-sensitive fluorescent dye assay. (3) Results: When compared to the CB₁ receptor full agonist WIN 55,212-2 and the partial agonist Δ⁹-THC, none of the minor cannabinoids caused a significant activation of G_i/GIRK channel signaling. However, Δ⁹-THCV and Δ⁸-THCV antagonized the effect of WIN 55,212-2 with half-maximal inhibitory concentrations (IC₅₀s) of 434 nM and 757 nM, respectively. Δ⁹-THCV antagonism of the CB₁ receptor was “ligand-dependent”; Δ⁹-THCV was more potent in inhibiting WIN 55,212-2 and 2-arachidonoylglycerol (2-AG) than Δ⁹-THC. (4) Conclusions: While none of the minor cannabinoids caused G_i/GIRK channel activation, Δ⁹-THCV antagonized the CB₁ receptor in an isomer- and ligand-dependent manner.