Tag: Cannabinoids

Phytocannabinoids in Cannabis sativa: Recent studies on biosynthetic enzymes

Taura F, Sirikantaramas S, Shoyama Y, Shoyama Y, Morimoto S (2007)

Chem Biodiv 4: 1649–1663

DOI: 10.1002/cbdv.200790145

Cannabinoids, which are found only in Cannabis sativa, are secondary metabolites featuring alkylresorcinol and monoterpene moieties in their molecules. More than 60 cannabinoids have been isolated from marijuana or fresh Cannabis leaves, and their pharmacological properties have been extensively investigated. Among them, D9 -tetrahydrocannabinol (THC) is the well-known psychoactive component of marijuana. In addition, this cannabinoid is shown to exert a variety of therapeutic activities such as the relief of nausea caused by cancer chemotherapy and the suppression of spasticity associated with multiple sclerosis. Furthermore, recent studies have demonstrated that THC activates two types of cannabinoid receptors (termed CB1 and CB2), which are expressed in the mammalian brain and immune cells, respectively. Thus, THC has attracted a great deal of attention. Besides THC, several cannabinoids also show various interesting activities, although they do not activate cannabinoid receptors. For example, cannabidiol (CBD), the isomer of THC, is a potent antioxidative and anti-inflammatory agent to provide neuroprotection in acute and chronic neurodegeneration. This cannabinoid is effective against the toxicity caused by 6-hydroxydopamine, which may be relevant to ParkinsonHs disease [9]. Cannabichromene (CBC) also shows various activities including anti-inflammatory, antifungal, and antibacterial activity. The co-action of CBC with THC was investigated, as marijuana contains a considerable amount of CBC. In addition, tetrahydrocannabivarin, the propyl homologue of THC in specific types of marijuana, is a cannabinoid CB1 and CB2 receptor antagonist. Since, in the 1990s, endogenous cannabinoid receptor ligands (endocannabinoids, e.g., anandamide and 2-arachidonoylglycerol) have been identified in mammalian tissues, cannabinoids from Cannabis sativa are now often called phytocannabinoids to distinguish them from endocannabinoids. Phytocannabinoids are classified into two types, i.e., neutral cannabinoids and cannabinoid acids, based on whether they contain a carboxy group or not. In the fresh Cannabis plants, cannabinoids are biosynthesized and accumulated as cannabinoid acids, and nonenzymatically decarboxylized into their neutral forms during storage and smoking. Several plausible hypotheses had been proposed for cannabinoid biosynthesis, and most of them were based on the presumption that tetrahydrocannabinolic acid (THCA) is biosynthesized by isomerization of cannabidiolic acid (CBDA), whereas CBDA and cannabichromenic acid (CBCA) are formed by oxidative cyclization of cannabigerolic acid (CBGA) [18]. To confirm the biosynthetic pathway, feeding experiments of radiolabeled precursors were attempted, but no clear results could be obtained due to low incorporation of radioactivity into cannabinoids. To overcome these difficulties, from the middle of 1990s, several research groups, including our laboratory, started to investigate the enzymes involved in cannabinoid biosynthesis, and successfully established the biosynthetic pathway of major phytocannabinoids as illustrated in Scheme 1. In the pathway, THCA, CBDA, and CBCA are biosynthesized from the common precursor CBGA by the action of unique oxidoreductases, i.e., THCA synthase, CBDA synthase, and CBCA synthase, respectively. On the other hand, CBGA is synthesized by alkylation of olivetolic acid (OLA) with geranylpyrophosphate (GPP) by a novel prenyltransferase called geranylpyrophosphate:olivatola te geranyltransferase (GOT) [24]. This article reviews individual biosynthetic enzymes and related topics.

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Phytocannabinoids: a unified critical inventory

Lum´ır Ondˇrej Hanuˇs, Stefan Martin Meyer, Eduardo Mu˜noz, Orazio Taglialatela-Scafatid and Giovanni Appendino

Natural Product Reports 2016 The Royal Society of Chemistry

DOI: 10.1039/c6np00074f

Cannabis sativa L. is a prolific, but not exclusive, producer of a diverse group of isoprenylated resorcinyl polyketides collectively known as phytocannabinoids. The modular nature of the pathways that merge into the phytocannabinoid chemotype translates in differences in the nature of the resorcinyl side-chain and the degree of oligomerization of the isoprenyl residue, making the definition of phytocannabinoid elusive from a structural standpoint. A biogenetic definition is therefore proposed, splitting the phytocannabinoid chemotype into an alkyl- and a b-aralklyl version, and discussing the relationships between phytocannabinoids from different sources (higher plants, liverworts, fungi). The startling diversity of cannabis phytocannabinoids might be, at least in part, the result of non-enzymatic transformations induced by heat, light, and atmospheric oxygen on a limited set of major constituents
(CBG, CBD, D9-THC and CBC and their corresponding acidic versions), whose degradation is detailed to emphasize this possibility. The diversity of metabotropic (cannabinoid receptors), ionotropic (thermosTRPs), and transcription factors (PPARs) targeted by phytocannabinoids is discussed. The integrated inventory of these compounds and their biological macromolecular end-points highlights the opportunities that phytocannabinoids offer to access desirable drug-like space beyond the one associated to the narcotic target CB1

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Pharmacogenetics of Cannabinoids

Szymon Hryhorowicz, Michal Walczak, Oliwia Zakerska-Banaszak, Ryszard Słomski, and Marzena Skrzypczak-Zielińska

Eur J Drug Metab Pharmacokinet. 2018; 43(1): 1–12.

doi: 10.1007/s13318-017-0416-z

Although the application of medical marijuana and cannabinoid drugs is controversial, it is a part of modern-day medicine. The list of diseases in which cannabinoids are promoted as a treatment is constantly expanding. Cases of significant improvement in patients with a very poor prognosis of glioma or epilepsy have already been described. However, the occurrence of side effects is still difficult to estimate, and the current knowledge of the therapeutic effects of cannabinoids is still insufficient. In our opinion, the answers to many questions and concerns regarding the medical use of cannabis can be provided by pharmacogenetics. Knowledge based on proteins and molecules involved in the transport, action, and metabolism of cannabinoids in the human organism leads us to predict candidate genes which variations are responsible for the presence of the therapeutic and side effects of medical marijuana and cannabinoid-based drugs. We can divide them into: receptor genes—CNR1, CNR2, TRPV1, and GPR55, transporters—ABCB1, ABCG2, SLC6A, biotransformation, biosynthesis, and bioactivation proteins encoded by CYP3A4, CYP2C19, CYP2C9, CYP2A6, CYP1A1, COMT, FAAH, COX2, ABHD6, ABHD12 genes, and also MAPK14. This review organizes the current knowledge in the context of cannabinoids pharmacogenetics according to individualized medicine and cannabinoid drugs therapy

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Pharmacokinetics and metabolism of the plant cannabinoids, delta9-tetrahydrocannabinol, cannabidiol and cannabinol

Huestis MA

Handb Exp Pharmacol. 2005;(168):657-90.

DOI: 10.1007/3-540-26573-2_23

Increasing interest in the biology, chemistry, pharmacology, and toxicology of cannabinoids and in the development of cannabinoid medications necessitates an understanding of cannabinoid pharmacokinetics and disposition into biological fluids and tissues. A drug’s pharmacokinetics determines the onset, magnitude, and duration of its pharmacodynamic effects. This review of cannabinoid pharmacokinetics encompasses absorption following diverse routes of administration and from different drug formulations, distribution of analytes throughout the body, metabolism by different tissues and organs, elimination from the body in the feces, urine, sweat, oral fluid, and hair, and how these processes change over time. Cannabinoid pharmacokinetic research has been especially challenging due to low analyte concentrations, rapid and extensive metabolism, and physicochemical characteristics that hinder the separation of drugs of interest from biological matrices–and from each other–and lower drug recovery due to adsorption of compounds of interest to multiple surfaces. delta9-Tetrahydrocannabinol, the primary psychoactive component of Cannabis sativa, and its metabolites 11-hydroxy-delta9-tetrahydrocannabinol and 11-nor-9-carboxy-tetrahydrocannabinol are the focus of this chapter, although cannabidiol and cannabinol, two other cannabinoids with an interesting array of activities, will also be reviewed. Additional material will be presented on the interpretation of cannabinoid concentrations in human biological tissues and fluids following controlled drug administration.

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Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb

Angelo A. Izzol, Francesca Borrelli, Raffaele Capasso1, Vincenzo Di Marzo, and Raphael Mechoulam

TIPS-730; No of Pages 13. 2009

doi: 10.1016/j.tips.2009.07.006

D9 -tetrahydrocannabinol binds cannabinoid (CB1 and CB2) receptors, which are activated by endogenous compounds (endocannabinoids) and are involved in a wide range of physiopathological processes (e.g. modulation of neurotransmitter release, regulation of pain perception, and of cardiovascular, gastrointestinal and liver functions). The well-known psychotropic effects of D9 – tetrahydrocannabinol, which are mediated by activation of brain CB1 receptors, have greatly limited its clinical use. However, the plant Cannabis contains many cannabinoids with weak or no psychoactivity that, therapeutically, might be more promising than D9 – tetrahydrocannabinol. Here, we provide an overview of the recent pharmacological advances, novel mechanisms of action, and potential therapeutic applications of such non-psychotropic plant-derived cannabinoids. Special emphasis is given to cannabidiol, the possible applications of which have recently emerged in inflammation, diabetes, cancer, affective and neurodegenerative diseases, and to D9 -tetrahydrocannabivarin, a novel CB1 antagonist which exerts potentially useful actions in the treatment of epilepsy and obesity.

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Non-cannabinoid constituents from a high potency Cannabis sativa variety

Radwan, M. M., ElSohly, M. A., Slade, D., Ahmed, S. A., Wilson, L., El-Alfy, A. T., Ross, S. A. 

Phytochemistry, 69(14), 2627–2633. (2008) 

doi: 10.1016/j.phytochem.2008.07.010

Six new non-cannabinoid constituents were isolated from a high potency Cannabis sativa L. variety, namely 5-acetoxy-6-geranyl-3-n-pentyl-1,4-benzoquinone (1), 4,5-dihydroxy-2,3,6-trimethoxy-9,10- dihydrophenanthrene (2), 4-hydroxy-2,3,6,7-tetramethoxy-9,10-dihydrophenanthrene (3), 4,7-dimethoxy-1,2,5-trihydroxyphenanthrene (4), cannflavin C (5) and b-sitosteryl-3-O-b-D-glucopyranoside-20 – O-palmitate (6). In addition, five known compounds, a-cannabispiranol (7), chrysoeriol (8), 6-prenylapigenin (9), cannflavin A (10) and b-acetyl cannabispiranol (11) were identified, with 8 and 9 being reported for the first time from cannabis. Some isolates displayed weak to strong antimicrobial, antileishmanial, antimalarial and anti-oxidant activities. Compounds 2–4 were inactive as analgesics.

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Natural cannabinoids: Templates for drug discovery

Ganesh Thakur, Rick Duclos, Alexandros Makriyannis

January 2006 Life Sciences 78(5):454-66

DOI: 10.1016/j.lfs.2005.09.014

Recent studies have elucidated the biosynthetic pathway of cannabinoids and have highlighted the preference for a C-3 n-pentyl side chain in the most prominently represented cannabinoids from Cannabis sativa and their medicinally important decarboxylation products. The corresponding C-3 n-propyl side chain containing cannabinoids are also found, although in lesser quantities. Structure-activity relationship (SAR) studies performed on Delta(9)-tetrahydrocannabinol (Delta(9)-THC), the key psychoactive ingredient of Cannabis, and its synthetic analogues have identified the C-3 side chain as the key pharmacophore for ligand affinity and selectivity for the known cannabinoid receptors and for pharmacological potency. Interestingly, the terminal n-pentyl saturated hydrocarbon side chain of endocannabinoids also plays a corresponding crucial role in conferring similar properties. This review briefly summarizes the biosynthesis of cannabinoids and endocannabinoids and focuses on their side chain SAR.

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Minor oxygenated cannabinoids from high potency Cannabis sativa L.

Safwat A. Ahmed, Samir A. Ross, Desmond Slade, Mohamed M. Radwan, Ikhlas A. Khan, Mahmoud A. ElSohly

Phytochemistry 117 (2015) 194–199

DOI: 10.1016/j.phytochem.2015.04.007

Nine oxygenated cannabinoids were isolated from a high potency Cannabis sativa L. variety. Structure elucidation was achieved using spectroscopic techniques, including 1D and 2D NMR, HRMS and GC–MS.
These minor compounds include four hexahydrocannabinols, four tetrahydrocannabinols, and one hydroxylated cannabinol, namely 9a-hydroxyhexahydrocannabinol, 7-oxo-9a-hydroxyhexa-hydrocannabinol,
10a-hydroxyhexahydrocannabinol, 10aR-hydroxyhexahydrocannabinol, D9-THC aldehyde A, 8-oxo-D9-THC, 10aa-hydroxy-10-oxo-D8-THC, 9a-hydroxy-10-oxo-D6a,10a-THC, and 10S-hydroxycannabinol, respectively. The latter compound showed moderate anti-MRSa (IC50 10.0 lg/mL), moderate antileishmanial (IC50 14.0 lg/mL) and mild antimalarial activity against Plasmodium falciparum (D6 clone) and P. falciparum (W2 clone) with IC50 values of 3.4 and 2.3 lg/mL, respectively.

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Microbial metabolism of cannflavin A and B isolated from Cannabis sativa

Ibrahim, A. K., Radwan, M. M., Ahmed, S. A., Slade, D., Ross, S. A., ElSohly, M. A., & Khan, I. A. 

Phytochemistry, 71(8-9), 1014-1019. (2010).
 
doi: 10.1016/j.phytochem.2010.02.011

Microbial metabolism of cannflavin A (1) and B (2), two biologically active flavonoids isolated from Cannabis sativa L., produced five metabolites (3–7). Incubation of 1 and 2 with Mucor ramannianus (ATCC 9628) and Beauveria bassiana (ATCC 13144), respectively, yielded 600S,700-dihydroxycannflavin A (3), 600S,700-dihydroxycannflavin A 7-sulfate (4) and 600S,700-dihydroxycannflavin A 40 -O-a-L-rhamnopyranoside (5), and cannflavin B 7-O-b-D-4000-O-methylglucopyranoside (6) and cannflavin B 7-sulfate (7), respectively. All compounds were evaluated for antimicrobial and antiprotozoal activity.

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