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

• Published in: Science advances Vol. 4; no. 10; p. eaat2166
• Main Authors: Chicca, A, Schafroth, M A, Reynoso-Moreno, I, Erni, R, Petrucci, V, Carreira, E M, Gertsch, J
• Format: Journal Article
• Language: English
• Published: United States American Association for the Advancement of Science 01.10.2018
• Subjects: Neurophysiology; Plant Sciences; SciAdv r-articles
• ISSN: 2375-2548; 2375-2548
• DOI: 10.1126/sciadv.aat2166

Phytochemical studies on the liverwort genus have previously identified the bibenzyl (-)- -perrottetinene ( -PET), which structurally resembles (-)-Δ - -tetrahydrocannabinol (Δ - -THC) from L. 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 (-)- -PET and its (-)- 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 (-)- -PET was profiled on major brain receptors, showing a selective cannabinoid pharmacology. This study also uncovers pharmacological differences between Δ -THC and PET diastereoisomers. Most notably, (-)- -PET and (-)- -PET significantly reduced basal brain prostaglandin levels associated with Δ - -THC side effects in a CB1 receptor-dependent manner, thus mimicking the action of the endocannabinoid 2-arachidonoyl glycerol. Therefore, the natural product (-)- -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 preparations as moderately active legal highs.