Early phytocannabinoid chemistry to endocannabinoids and beyond

Mechoulam, Raphael; Hanŭs, L; Pertwee, Roger G.; Howlett, Allyn C.

doi:10.1038/nrn3811

Cited by 305 publications

(244 citation statements)

References 101 publications

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“…A final working solution was prepared with 100 nM AEA-d8, NADA-d8, DHEA-d4 and 1,000 nM 2-AG-d8, SEA-d3, PEA-d4, LEA-d3, and OEA-d4. ethanolamine) and 2-arachidonoylglycerol (2-AG) are the two best studied endocannabinoids (9). They are synthesized on demand from membrane lipids in a stimulus-dependent manner and are degraded by fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), respectively (10,11).…”

Section: Preparation Of Standards and Internal Standardsmentioning

confidence: 99%

Quantitative profiling of endocannabinoids and related N-acylethanolamines in human CSF using nano LC-MS/MS

Kantae

Ogino

Noga

et al. 2017

Journal of Lipid Research

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The endocannabinoid system has emerged as a crucial regulator of synaptic communication in the CNS (1-3). Dysregulation of this system is implicated in various neurological and psychiatric disorders, such as neuroinflammation, stroke, brain trauma, anxiety, and depression (4-8). The endocannabinoid system consists of endogenous lipid messengers (endocannabinoids) that activate two distinct cannabinoid (CB) (CB 1 and CB 2 ) receptors and the en-

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Section: Preparation Of Standards and Internal Standardsmentioning

confidence: 99%

Quantitative profiling of endocannabinoids and related N-acylethanolamines in human CSF using nano LC-MS/MS

Kantae

Ogino

Noga

et al. 2017

Journal of Lipid Research

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“…The phytocannabinoids (CANN) are a group of related compounds extracted from the cannabis plant (1). The archetypal CANN that is most widely known is ∆9-tetrahydrocannabinol (THC).…”

Section: Introductionmentioning

confidence: 99%

Anticancer effects of phytocannabinoids used with chemotherapy in leukaemia cells can be improved by altering the sequence of their administration

Scott

Dalgleish

Liu

2017

International Journal of Oncology

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Abstract. Phytocannabinoids possess anticancer activity when used alone, and a number have also been shown to combine favourably with each other in vitro in leukaemia cells to generate improved activity. We have investigated the effect of pairing cannabinoids and assessed their anticancer activity in cell line models. Those most effective were then used with the common anti-leukaemia drugs cytarabine and vincristine, and the effects of this combination therapy on cell death studied in vitro. Results show a number of cannabinoids could be paired together to generate an effect superior to that achieved if the components were used individually. For example, in HL60 cells, the IC 50 values at 48 h for cannabidiol (CBD) and tetrahydrocannabinol (THC) when used alone were 8 and 13 µM, respectively; however, if used together, it was 4 µM. Median-effect analysis confirmed the benefit of using cannabinoids in pairs, with calculated combination indices being <1 in a number of cases. The most efficacious cannabinoid-pairs subsequently synergised further when combined with the chemotherapy agents, and were also able to sensitise leukaemia cells to their cytotoxic effects. The sequence of administration of these drugs was important though; using cannabinoids after chemotherapy resulted in greater induction of apoptosis, whilst this was the opposite when the schedule of administration was reversed. Our results suggest that when certain cannabinoids are paired together, the resulting product can be combined synergistically with common anti-leukaemia drugs allowing the dose of the cytotoxic agents to be dramatically reduced yet still remain efficacious. Nevertheless, the sequence of drug administration is crucial to the success of these triple combinations and should be considered when planning such treatments.

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“…Compound 5 (HU-444) was first investigated for its possible THC-like psychoactivity in the tetrad assay, which measures cannabinoid-induced hypokinesia, hypothermia, and antinociception in a tail flick or hot plate test in mice (Martin et al, 1991;Fride and Mechoulam, 1993;Mechoulam et al, 2014). The mouse tetrad serves as a useful in vivo screen for psychotropic cannabinoids, which, in contrast to many other types of drugs, displays potency in all four of these bioassays.…”

Section: Resultsmentioning

confidence: 99%

HU-444, a Novel, Potent Anti-Inflammatory, Nonpsychotropic Cannabinoid

Haj

Sumariwalla

Hanŭs

et al. 2015

J Pharmacol Exp Ther

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Cannabidiol (CBD) is a component of cannabis, which does not cause the typical marijuana-type effects, but has a high potential for use in several therapeutic areas. In contrast to D 9 -tetrahydrocannabinol (D 9 -THC), it binds very weakly to the CB1 and CB2 cannabinoid receptors. It has potent activity in both in vitro and in vivo anti-inflammatory assays. Thus, it lowers the formation of tumor necrosis factor (TNF)-a, a proinflammatory cytokine, and was found to be an oral antiarthritic therapeutic in murine collagen-induced arthritis in vivo. However, in acidic media, it can cyclize to the psychoactive D 9 -THC. We report the synthesis of a novel CBD derivative, HU-444, which cannot be converted by acid cyclization into a D 9-THC-like compound. In vitro HU-444 had anti-inflammatory activity (decrease of reactive oxygen intermediates and inhibition of TNF-a production by macrophages); in vivo it led to suppression of production of TNF-a and amelioration of liver damage as well as lowering of mouse collagen-induced arthritis. HU-444 did not cause D 9-THC-like effects in mice. We believe that HU-444 represents a potential novel drug for rheumatoid arthritis and other inflammatory diseases.

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Early phytocannabinoid chemistry to endocannabinoids and beyond

Cited by 305 publications

References 101 publications

Quantitative profiling of endocannabinoids and related N-acylethanolamines in human CSF using nano LC-MS/MS

Quantitative profiling of endocannabinoids and related N-acylethanolamines in human CSF using nano LC-MS/MS

Anticancer effects of phytocannabinoids used with chemotherapy in leukaemia cells can be improved by altering the sequence of their administration

HU-444, a Novel, Potent Anti-Inflammatory, Nonpsychotropic Cannabinoid

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