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

Chicca, Andrea; Schafroth, Michael A.; Reynoso-Moreno, Inés; Erni, Reto; Petrucci, Vanessa; Carreira, Erick M.; Gertsch, Jürg

doi:10.1126/sciadv.aat2166

Cited by 58 publications

(90 citation statements)

References 44 publications

(82 reference statements)

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“…(Radulaceae), liverworts that are native to the northern island of New Zealand. These bibenzyl analogs of Δ 9 -THC, (−)-cis-perrottetinene, and (−)-cisperrottetinenic acid are noteworthy for their inverted stereoconfiguration compared to nonbryophyte cannabinoids [16][17][18][19].…”

Section: Illustration Of the Structural Characteristics Of Cannabinoimentioning

confidence: 99%

Phytocannabinoids: Origins and Biosynthesis

Gülck

Møller

2020

Trends in Plant Science

241

240

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Phytocannabinoids are bioactive natural products found in some flowering plants, liverworts, and fungi that can be beneficial for the treatment of human ailments such as pain, anxiety, and cachexia. Targeted biosynthesis of cannabinoids with desirable properties requires identification of the underlying genes and their expression in a suitable heterologous host. We provide an overview of the structural classification of phytocannabinoids based on their decorated resorcinol core and the bioactivities of naturally occurring cannabinoids, and we review current knowledge of phytocannabinoid biosynthesis in Cannabis, Rhododendron, and Radula species. We also highlight the potential in planta roles of phytocannabinoids and the opportunity for synthetic biology approaches based on combinatorial biochemistry and protein engineering to produce cannabinoid derivatives with improved properties. Phytocannabinoids The term phytocannabinoid (see Glossary, also cannabinoid) defines meroterpenoids with a resorcinyl core typically decorated with a para-positioned isoprenyl, alkyl, or aralkyl side chain [1]. The alkyl side chain typically contains an odd number of carbon atoms, where orcinoids contain one carbon, varinoids three, and olivetoids five. Cannabinoids with an even number of carbon atoms in the side chain are known but rare. The term cannabinoid generally refers to molecules with a characteristic chemical structure; however, the term may also refer to pharmacological ligands of human endocannabinoid receptors [2]. In this review we use the chemical definition of cannabinoids. Phytocannabinoids occur in flowering plants, liverworts, and fungi (Figure 1, Key Figure). They were first isolated from Cannabis sativa L. (Cannabaceae), a plant with a long and controversial history of use and abuse [3]. The mammalian brain has receptors that respond to compounds found in C. sativa. Accordingly, these receptors were named cannabinoid receptors (CB x) and are the basis of the endocannabinoid system. Studies in human and animals demonstrated that the endocannabinoid system regulates a broad range of biological functions, including memory, mood, brain reward systems, and drug addiction, as well as metabolic processes such as lipolysis, glucose metabolism, and energy balance [2]. More than 113 different cannabinoids have been isolated from C. sativa and these are classified into distinct types: cannabigerols (CBGs), cannabichromenes (CBCs), cannabidiols (CBDs), (−)-Δ 9-trans-tetrahydrocannabinols (Δ 9-THCs), (−)-Δ 8-trans-tetrahydrocannabinols (Δ 8-THCs), cannabicyclols (CBLs), cannabielsoins (CBEs), cannabinols (CBNs), cannabinodiols (CBNDs), cannabitriols (CBTs), and the miscellaneous cannabinoids (Figure 2) [4]. C. sativa predominantly produces alkyl type cannabinoids that carry a monoterpene isoprenyl moiety (C10) and a pentyl side chain (C5) [1]. The most abundant constituents are trans-Δ 9-THC, CBD, CBC, and CBG, together with their respective acid forms (Δ 9-THCA, CBDA, CBCA, and CBGA) [5]. Cannabinoid biosynthetic pathways ty...

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Section: Illustration Of the Structural Characteristics Of Cannabinoimentioning

confidence: 99%

Phytocannabinoids: Origins and Biosynthesis

Gülck

Møller

2020

Trends in Plant Science

241

240

View full text Add to dashboard Cite

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“…Similar phenomenon could be observed for bibenzyl cannabinoids isolated primarily from different species of genus Radula. Notably, Radula preparations are also popular as "legal-high" due to high cannabinoid content [105]. The cannabinoids, (extracted from C. sativa and other angiosperms), extensively studied for psycho-active efficacy but the natural compound perrottetinene acid and its decarboxylated form perrottetinene, (harvested from bryophyte), have not been studied well and thus their pharmacological applications are not validated scientifically [103].…”

Section: Discussionmentioning

confidence: 99%

“…This represents bibenzyl iso-tetrahydro cannabinoids from Radula species [ 12 , 75 ]. Total synthesis of (−)-cis-perrottetinene and its in vitro pharmacological activity on experimental BALB/c mice model have also been documented [ 105 ]. They demonstrated the ability of both cis-perrottetinene and Δ9-trans-tetrahydrocannabinol are to trigger hypothermic response by affecting expression of cannabinoid receptors (human cannabinoid receptor type 1, CB1R).…”

Section: Bibenzyl Cannabinoids: Therapeutically Most Studied Derivatimentioning

confidence: 99%

“…They demonstrated the ability of both cis-perrottetinene and Δ9-trans-tetrahydrocannabinol are to trigger hypothermic response by affecting expression of cannabinoid receptors (human cannabinoid receptor type 1, CB1R). Moreover, these compounds affect activity of endocannabinoid-degrading enzymes [ 105 ]. Cannabinoid type drugs are presently recommended for many neurodegenerative disorder, anti-neoplastic chemotherapy, post-traumatic stress (PTS), epilepsy, multiple sclerosis etc.…”

Section: Bibenzyl Cannabinoids: Therapeutically Most Studied Derivatimentioning

confidence: 99%

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Bibenzyls and bisbybenzyls of bryophytic origin as promising source of novel therapeutics: pharmacology, synthesis and structure-activity

Nandy

Dey

2020

DARU J Pharm Sci

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Background The amphibian, non-vascular, gametophyte-dominant, bio-indicator class, bryophytes; with their wide ranges of habitat have attained importance due to their promising medicinal attributions and therapeutic role; mostly aided by presence of aromatic bibenzyl and bisbybenzyl class of compounds. Bibenzyls are steroidal ethane derivatives, resembling the structural moiety of bioactive dihydro-stilbenoids or iso-quinoline alkaloids. These stress triggered secondary metabolites are the byproducts of the flavonoid biosynthetic pathway. Different classes of bryophytes (Bryophyta, Marchantiophyta and Anthocerotophyta) possess different subtypes of bibenzyls and dimeric bisbibenzyls. Among the liverwort, hornwort and mosses, former one is mostly enriched with bibenzyl type constituents as per the extensive study conducted for phytochemical deposit. Considering macrocyclic and acyclic group of bibenzyls and bisbybenzyls, generally marchantin type compounds are reported vividly for significant biological activity that includes neuro-nephro-cardio-protection besides anti-allergic, anti-microbial, anti-apoptotic and cytotoxic activities studied on in-vitro and in-vivo models or on cell lines. Result The critical analysis of reported chemical and pharmaceutical attributions of bibenzyls and bis-bibenzyls yielded detailed report on this compound class along with their application, mode of action, natural source, techniques of synthesis, extraction procedure, isolation and characterization. Further, the structure activity relationship studies and bioactivity of bibenzyls derived from non-bryophytic origin were also summarized. Conclusion This review encompasses prospective biological application of botanical reservoir of this primarily ignored, primeval land plant group where recent technical advances has paved the way for qualitative and quantitative isolation and estimation of novel compounds as well as marker components to study their impact on environment, as bio-control agents and as key leads in future drug designing.

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“…[78][79][80] Alternatively, the groups of Carreira and Studer have disclosed stereodivergent syntheses of cannabinoids, affording a variety of cannabinoids by varying catalyst ligands. [81][82][83] This latter approach may provide fast access into more stereodiverse cannabinoids.…”

Section: Outlook and Conclusionmentioning

confidence: 99%