A novel phytocannabinoid isolated from Cannabis sativa L. with an in vivo cannabimimetic activity higher than Δ ⁹-tetrahydrocannabinol: Δ ⁹-Tetrahydrocannabiphorol

Abstract

(-)- Trans-Δ ⁹-tetrahydrocannabinol (Δ ⁹-THC) is the main compound responsible for the intoxicant activity of Cannabis sativa L. The length of the side alkyl chain influences the biological activity of this cannabinoid. In particular, synthetic analogues of Δ ⁹-THC with a longer side chain have shown cannabimimetic properties far higher than Δ ⁹-THC itself. In the attempt to define the phytocannabinoids profile that characterizes a medicinal cannabis variety, a new phytocannabinoid with the same structure of Δ ⁹-THC but with a seven-term alkyl side chain was identified. The natural compound was isolated and fully characterized and its stereochemical configuration was assigned by match with the same compound obtained by a stereoselective synthesis. This new phytocannabinoid has been called (-)- trans-Δ ⁹-tetrahydrocannabiphorol (Δ ⁹-THCP). Along with Δ ⁹-THCP, the corresponding cannabidiol (CBD) homolog with seven-term side alkyl chain (CBDP) was also isolated and unambiguously identified by match with its synthetic counterpart. The binding activity of Δ ⁹-THCP against human CB ₁ receptor in vitro (K _i = 1.2 nM) resulted similar to that of CP55940 (K _i = 0.9 nM), a potent full CB ₁ agonist. In the cannabinoid tetrad pharmacological test, Δ ⁹-THCP induced hypomotility, analgesia, catalepsy and decreased rectal temperature indicating a THC-like cannabimimetic activity. The presence of this new phytocannabinoid could account for the pharmacological properties of some cannabis varieties difficult to explain by the presence of the sole Δ ⁹-THC.