Publication Date:
2018-10-25
Description:
Phytochemical studies on the liverwort Radula genus have previously identified the bibenzyl (–)- cis -perrottetinene ( cis -PET), which structurally resembles (–)- 9 - trans -tetrahydrocannabinol ( 9 - trans -THC) from Cannabis sativa L. Radula 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 (–)- cis -PET and its (–)- trans 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 (–)- cis -PET was profiled on major brain receptors, showing a selective cannabinoid pharmacology. This study also uncovers pharmacological differences between 9 -THC and PET diastereoisomers. Most notably, (–)- cis -PET and (–)- trans -PET significantly reduced basal brain prostaglandin levels associated with 9 - trans -THC side effects in a CB1 receptor–dependent manner, thus mimicking the action of the endocannabinoid 2-arachidonoyl glycerol. Therefore, the natural product (–)- cis -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 Radula preparations as moderately active legal highs.
Electronic ISSN:
2375-2548
Topics:
Natural Sciences in General
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