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

• Published in: Journal of pharmacy and pharmacology 2019-12, Vol.71 (12), p.1879-1889
• Main Authors: El‐Alfy, Abir T., Abourashed, Ehab A., Patel, Christina, Mazhari, Nunmoula, An, HeaRe, Jeon, Andrew
• Format: Article
• Language: English
• 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
• ISSN: 0022-3573; 2042-7158
• DOI: 10.1111/jphp.13174

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