The Macamide N-3-Methoxybenzyl-Linoleamide Is a Time-Dependent Fatty Acid Amide Hydrolase (FAAH) Inhibitor

Abstract

The Peruvian plant Lepidium meyenii (Maca) has been shown to possess neuroprotective activity both in vitro and in vivo. Previous studies have also demonstrated the activity of the pentane extract and its macamides, the most representative lipophilic constituents of Maca, in the endocannabinoid system as fatty acid amide hydrolase (FAAH) inhibitors. One of the most active macamides, N-3-methoxybenzyl-linoleamide, was studied to determine its mechanism of interaction with FAAH and whether it has inhibitory activity on mono-acyl glycerol lipase (MAGL), the second enzyme responsible for endocannabinoid degradation. Macamide concentrations from 1 to 100 μM were tested using FAAH and MAGL inhibitor assay methods and showed no effect on MAGL. Tests with other conditions were performed in order to characterize the inhibitory mechanism of FAAH inhibition. N-3-methoxybenzyl-linoleamide displayed significant time-dependent and dose-dependent FAAH inhibitory activity. The mechanism of inhibition was most likely irreversible or slowly reversible. These results suggest the potential application of macamides isolated from Maca as FAAH inhibitors, as they might act on the central nervous system to provide analgesic, anti-inflammatory, or neuroprotective effects, by modulating the release of neurotransmitters.

Effects of a water extract of Lepidium meyenii root in different models of persistent pain in rats

“…Anandamide is involved in several physiological processes such as painful sensitivity and neuroprotection [16]. Selective FAAH inhibitors enhance anandamide endogenous levels that cause antinociceptive effect by agonism on the CB 2 receptor [21].…”

“…On the contrary, limited evidence of efficacy against persistent pain has been described up to now [15]. However, in vitro studies confirmed macaenes family components' involvement in enhancing cannabinoid transmission [16]. The cholinergic stimulation induced by L. meyenii extract (mainly by polyphenols) has been related to memory improvement [17] as well as antioxidant properties that may sustain the antidepressant-like effects of the plant extract [18].…”

An ethnopharmacological survey conducted in the Bolivian Amazon, and identification of N-alkylamides and lignans from Lepidium meyenii and Heliopsis helianthoides var. scabra with effects on the central nervous system

“…103 It has been shown that the macamide N-3-methoxybenzyl linoleamide weakly inhibits the major AEA degrading enzyme fatty acid amide hydrolase (FAAH, which is a membrane bound mammalian enzyme responsible for the destruction of a number of endogenous signaling amides by hydrolysis), and may thus exert indirect cannabimimetic neuroprotective effects. 75 This was recently confirmed in a study in which synthesized macamides and analogs were shown to act as FAAH inhibitors, although no further ECS targets were tested. 76 In some pharmacological experiments, the sexual behaviour of male rats and the erectile function of castrated rats were enhanced.…”

“…68 While the interactions of Echinacea NAAs with CB receptors have been studied in more detail, ECS-interacting NAAs from other plants have been described only recently. 72,73,75,76 The assumption that NAAs may interfere with the ECS due to their structural similarity to endocannabinoids such as anandamide (N-arachidonoylethanolamide, AEA) and palmitoylethanolamide 35 is intuitive, but the confirmation of this assumption is hampered by the lack of structure -activity relationship (SAR) data.…”

“…Only macamide 3 showed a low micromolar inhibition of FAAH (IC 50 = 4.07 µM), as expected. 75 a Data are mean values from at least three independent experiments, and the 95% confidence interval (CI) is shown; OMDM-2 and UCM-707 were used as positive controls for AEA uptake. n.d., not determined.…”