Identification of Endocannabinoid System-Modulating N-Alkylamides from Heliopsis helianthoides var. scabra and Lepidium meyenii

Abstract

The discovery of the interaction of plant-derived N-alkylamides (NAAs) and the mammalian endocannabinoid system (ECS) and the existence of a plant endogenous Nacylethanolamine signaling system have led to the re-evaluation of this group of compounds. Herein, the isolation of seven NAAs and the assessment of their effects on major protein targets in the ECS network are reported. Four NAAs, octadeca-2E,4E,8E,10Z,14Z-pentaene-12-ynoic acid isobutylamide (1), octadeca-2E,4E,8E,10Z,14Z-pentaene-12-ynoic acid 2′-methylbutylamide (2), hexadeca-2E,4E,9Z-triene-12,14-diynoic acid isobutylamide (3), and hexadeca-2E,4E,9,12-tetraenoic acid 2′methylbutylamide (4), were identified from Heliopsis helianthoides var. scabra. Compounds 2−4 are new natural products, while 1 was isolated for the first time from this species. The previously described macamides, N-(3-methoxybenzyl)-(9Z,12Z,15Z)-octadecatrienamide (5), N-benzyl-(9Z,12Z,15Z)-octadecatrienamide (6), and N-benzyl-(9Z,12Z)-octadecadienamide (7), were isolated from Lepidium meyenii (Maca). N-Methylbutylamide 4 and N-benzylamide 7 showed submicromolar and selective binding affinities for the cannabinoid CB 1 receptor (K i values of 0.31 and 0.48 μM, respectively). Notably, compound 7 also exhibited weak fatty acid amide hydrolase (FAAH) inhibition (IC 50 = 4 μM) and a potent inhibition of anandamide cellular uptake (IC 50 = 0.67 μM) that was stronger than the inhibition obtained with the controls OMDM-2 and UCM707. The pronounced ECS polypharmacology of compound 7 highlights the potential involvement of the arachidonoyl-mimicking 9Z,12Z double-bond system in the linoleoyl group for the overall cannabimimetic action of NAAs. This study provides additional strong evidence of the endocannabinoid substrate mimicking of plant-derived NAAs and uncovers a direct and indirect cannabimimetic action of the Peruvian Maca root.

Alkamides: a critical reconsideration of a multifunctional class of unsaturated fatty acid amides

“…Due to the structural similarities of the 9,12 double-bond system of the lineleoyl group in 27t with anandamide the results provided additional strong evidence of the endocannabinoid substrate mimicking of some alkamides (Fig. 8) (Hajdu et al 2014). …”

“…The affinity of alkamides to cannabinoid receptors was shown to depend on their solubility and thus it is important to understand their physicochemical behavior in an aqueous environment. Raduner et al (2007) (Hajdu et al 2014). The newly described alkamides Alk 1-3 are not listed in Tables 2, 3 and 4 Phytochem Rev has no affinity to cannabinoid receptors) or for structurally related endogenous cannabinoids, such as anandamide (Fig.…”

Endocannabinoid Transport Revisited

“…However, the primary target of guineensine has not yet been identified though the pharmacological data (indirect cannabimimetic effects) strongly suggest that it targets the putative EMT. Another recently identified compound in the list of plant-derived natural AEA uptake inhibitors is the Nbenzyl-(9Z,12Z)-octadecadieneamide (macamide 7 in Table 1), which not only exhibits a nanomolar IC 50 value for AEA uptake inhibition but also inhibits FAAH at low micromolar concentrations (Hajdu et al, 2014). Furthermore, an analog of the natural product farinosone-C (BSL-34 in Table 1) was found to be a more selective inhibitor of AEA uptake (IC 50 value ¼ 232 nM (131-394 nM)) over FAAH inhibition (IC 50 > 10 μM), with close structural similarity to OMDM-2 (Burch et al, 2014).…”

Lepidium meyenii

“…Macamides N -benzylpalmitamide, N -benzyloleamide and N -(3-methoxybenzyl) palmitamide were isolated from maca pentane extract (Alquraini et al 2014 ). Hadju et al ( 2014 ) isolated the following macamides ( N -alkylamides) from maca roots:…”

“…Of the macamides (N-alkylamides) isolated from maca roots, N -(3-methoxybenzyl)-(9 Z ,12 Z ,15 Z )-octadecatrienamide (5), N -benzyl-(9 Z ,12 Z ,15 Z )-octadecatrienamide (6), and N -benzyl-(9 Z ,12 Z )-octadecadienamide (7), compound 7 showed submicromolar and selective binding affi nities for the cannabinoid CB1 receptor (Ki value of 0.48 μM) (Hadju et al 2014 ). Notably, compound 7 also exhibited weak fatty acid amide hydrolase (FAAH) inhibition (IC 5 0 = 4 μM) and a potent inhibition of anandamide cellular uptake (IC 50 = 0.67 μM).…”