Phenolic compounds from nutmeg (Myristica fragrans Houtt.) inhibit the endocannabinoid‐modulating enzyme fatty acid amide hydrolase

Objectives The study aimed to identify nutmeg compounds that indirectly interact with the endocannabinoid system through inhibition of the fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) enzymes. Methods Thirteen compounds were screened for FAAH and MAGL inhibition. Compounds de...

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Bibliographic Details
Published in:	Journal of pharmacy and pharmacology Vol. 71; no. 12; pp. 1879 - 1889
Main Authors:	El‐Alfy, Abir T., Abourashed, Ehab A., Patel, Christina, Mazhari, Nunmoula, An, HeaRe, Jeon, Andrew
Format:	Journal Article
Language:	English
Published:	England Wiley Subscription Services, Inc 01-12-2019 Oxford University Press
Subjects:	Amidohydrolases - antagonists & inhibitors Animal models Animals Anti-Anxiety Agents - administration & dosage Anti-Anxiety Agents - isolation & purification Anti-Anxiety Agents - pharmacology Anxiety Anxiety - drug therapy Anxiety - physiopathology Cannabinoids Disease Models, Animal Endocannabinoid system Endocannabinoids - metabolism Enzyme Inhibitors - administration & dosage Enzyme Inhibitors - isolation & purification Enzyme Inhibitors - pharmacology Fatty acids Fatty-acid amide hydrolase Hydrolase Inhibitory Concentration 50 licarin A Lipase Locomotor activity malabaricone C Male Maze Learning - drug effects Mice Monoacylglycerol Lipases - antagonists & inhibitors Myristica - chemistry Myristica fragrans Nutmeg Phenolic compounds Phenols Phenols - administration & dosage Phenols - isolation & purification Phenols - pharmacology Research Paper Selectivity Myristica fragrans malabaricone C fatty acid amide hydrolase licarin A nutmeg
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Summary:	Objectives The study aimed to identify nutmeg compounds that indirectly interact with the endocannabinoid system through inhibition of the fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) enzymes. Methods Thirteen compounds were screened for FAAH and MAGL inhibition. Compounds demonstrating significant FAAH inhibition were evaluated to determine the halfmaximal inhibitory concentration (IC50). The most potent compound was investigated in the elevated plus maze (EPM) rodent anxiety model. Key findings Three compounds, licarin A (9), 5′‐methoxylicarin A (8) and malabaricone C (6) were most active in inhibiting FAAH with IC50 of 7.02 μm ± 2.02, 4.57 μm ± 0.66 and 38.29 μm ± 6.18, respectively. None of the purified compounds showed significant MAGL inhibition. Because of its relative high potency and selectivity, compound 8 was further evaluated in the EPM animal model of anxiety. The compound showed significant increase in number of open arm entries (P < 0.05) when administered at 120 mg/kg dose. No effect was observed on the locomotor activity. Conclusions Results collected introduce active nutmeg compounds as potential leads for further development. Of the three compounds, 8 possesses highest potency and FAAH selectivity as well as anxiolytic activity. Furthermore, in vivo testing in appropriate behavioural animal paradigms is warranted.
ISSN:	0022-3573 2042-7158
DOI:	10.1111/jphp.13174