Uncovering the psychoactivity of a cannabinoid from liverworts associated with a legal high.

Abstract

Phytochemical studies on the liverwort <i>Radula</i> genus have previously identified the bibenzyl (-)-<i>cis</i>-perrottetinene (<i>cis</i>-PET), which structurally resembles (-)-Δ⁹-<i>trans</i>-tetrahydrocannabinol (Δ⁹-<i>trans</i>-THC) from <i>Cannabis sativa</i> L. <i>Radula</i> preparations are sold as cannabinoid-like legal high on the internet, even though pharmacological data are lacking. Herein, we describe a versatile total synthesis of (-)-<i>cis</i>-PET and its (-)-<i>trans</i> diastereoisomer and demonstrate that both molecules readily penetrate the brain and induce hypothermia, catalepsy, hypolocomotion, and analgesia in a CB1 receptor-dependent manner in mice. The natural product (-)-<i>cis</i>-PET was profiled on major brain receptors, showing a selective cannabinoid pharmacology. This study also uncovers pharmacological differences between Δ⁹-THC and PET diastereoisomers. Most notably, (-)-<i>cis</i>-PET and (-)-<i>trans</i>-PET significantly reduced basal brain prostaglandin levels associated with Δ⁹-<i>trans</i>-THC side effects in a CB1 receptor-dependent manner, thus mimicking the action of the endocannabinoid 2-arachidonoyl glycerol. Therefore, the natural product (-)-<i>cis</i>-PET is a psychoactive cannabinoid from bryophytes, illustrating the existence of convergent evolution of bioactive cannabinoids in the plant kingdom. Our findings may have implications for bioprospecting and drug discovery and provide a molecular rationale for the reported effects upon consumption of certain <i>Radula</i> preparations as moderately active legal highs.