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Inhibition of Fatty Acid Amide Hydrolase (FAAH) by Macamides
M Alasmari1, M Bӧhlke1, C Kelley1
1Department of Pharmaceutical Sciences, MCPHS University, 179 Longwood Ave., Boston, MA, 02115, USA.
Abstract:
The pentane extract of the Peruvian plant, Lepidium meyenii (Maca), has been demonstrated to possess neuroprotective activity in previous in vitro and in vivo studies (Pino-Figueroa et al. in Ann N Y Acad Sci 1199:77-85, 2010; Pino-Figueroa et al. in Am J Neuroprot Neuroregener 3:87-92, 2011). This extract contains a number of macamides that may act on the endocannabinoid system (Pino-Figueroa et al. in Ann N Y Acad Sci 1199:77-85, 2010; Pino-Figueroa et al., 2011; Dini et al. in Food Chem 49:347-349, 1994). The aim of this study was to characterize the inhibitory activity of four of these maccamides (N-benzylstearamide, N-benzyloleamide, N-benzyloctadeca-9Z,12Z-dienamide, and N-benzyloctadeca-9Z,12Z,15Z-trienamide) on fatty acid amide hydrolase (FAAH), an enzyme that is responsible for endocannabinoid degradation in the nervous system (Kumar et al. in Anaesthesia 56:1059-1068, 2001). The four compounds were tested at concentrations between 1 and 100 μM, utilizing an FAAH inhibitor screening assay. The results demonstrated concentration-dependent FAAH inhibitory activities for the four macamides tested. N-Benzyloctadeca-9Z,12Z-dienamide demonstrated the highest FAAH inhibitory activity whereas N-benzylstearamide had the lowest inhibitory activity. In addition, N-benzylstearamide, N-benzyloleamide, and N-benzyloctadeca-9Z,12Z-dienamide demonstrated time-dependent inhibition when tested after a pre-incubation period, indicating that the mechanism of inhibition for these compounds most likely is irreversible. Of interest, unsaturation in the fatty acid moiety resulted in greater FAAH inhibitory activity. LC/MS/MS analysis demonstrated that FAAH was able to hydrolyze N-benzyloctadeca-9Z,12Z-dienamide, suggesting that N-benzyloctadeca-9Z,12Z-dienamide is also a slow substrate for FAAH. These results provide useful information about the mechanism of action of Lepidium meyenii and may help with the development of new compounds with FAAH inhibitory or modulatory activity.
Insights
Maca plant extracts contain macamides that inhibit fatty acid amide hydrolase (FAAH), an enzyme breaking down endocannabinoids. This study characterized four macamides, finding they inhibit FAAH in a concentration-dependent manner, with potential for new therapeutic compounds.
Area of Science:
- Neuroscience
- Pharmacology
- Phytochemistry
Background:
- Lepidium meyenii (Maca) pentane extract exhibits neuroprotective effects.
- Maca contains macamides potentially acting on the endocannabinoid system.
- Fatty acid amide hydrolase (FAAH) degrades endocannabinoids in the nervous system.
Purpose of the Study:
- To characterize the inhibitory activity of four Maca-derived macamides on FAAH.
- To investigate the mechanism of FAAH inhibition by these compounds.
Main Methods:
- Tested four macamides (N-benzylstearamide, N-benzyloleamide, N-benzyloctadeca-9Z,12Z-dienamide, and N-benzyloctadeca-9Z,12Z,15Z-trienamide) using an FAAH inhibitor screening assay.
- Evaluated compounds at concentrations from 1 to 100 μM.
- Utilized LC/MS/MS analysis to assess substrate hydrolysis.
Main Results:
- All four tested macamides demonstrated concentration-dependent FAAH inhibitory activity.
- N-Benzyloctadeca-9Z,12Z-dienamide showed the highest inhibitory activity; N-benzylstearamide showed the lowest.
- Three compounds exhibited time-dependent inhibition, suggesting irreversible mechanisms.
- Increased unsaturation in the fatty acid chain correlated with enhanced FAAH inhibition.
Conclusions:
- Maca-derived macamides are potent inhibitors of FAAH.
- The mechanism of inhibition for some macamides is likely irreversible.
- These findings offer insights into Maca's mechanism of action and potential for developing novel FAAH modulators.
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