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N‐(Pyridine‐3‐ylmethyl)oleamide (NPMO) as a new inhibitor of fatty acid amide hydrolase (FAAH)
Author(s) -
Alafnan Ahmed,
Wu Hui,
Bohlke Mark,
Maher Timothy,
PinoFigueroa Alejandro
Publication year - 2015
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.29.1_supplement.770.7
Subject(s) - fatty acid amide hydrolase , endocannabinoid system , anandamide , chemistry , amidase , ic50 , pharmacology , neuroprotection , biochemistry , enzyme , non competitive inhibition , in vivo , inhibitory postsynaptic potential , stereochemistry , in vitro , cannabinoid receptor , biology , antagonist , endocrinology , receptor , microbiology and biotechnology
Fatty acid amide hydrolase (FAAH) is one of the enzymes responsible for terminating endocannabinoid signaling in the CNS and periphery. The objective of this study was to determine and characterize the inhibitory effects of N‐(pyridine‐3‐ylmethyl)oleamide (NPMO) on FAAH. NPMO is a synthetic analog of the macamides present in Lepidium meyenii (Maca), a Peruvian plant with demonstrated neuroprotective effects in vitro and in vivo. Recent studies have also demonstrated that Maca extracts have activity on the endocannabinoid system and inhibitory activity on FAAH. In this study NPMO, from 2 to 100 µM, was tested using an FAAH inhibitor screening assay method. The results demonstrated that NPMO possesses concentration‐dependent FAAH inhibitory activity with anapproximate IC 50 of 24.4 µM. Michaelis‐Menten and Lineweaver‐Burk plot analyses revealed that NPMO decreased the enzyme V max from 1.57±0.09 to 0.58±0.04 pmol/min with increasing NPMO concentrations, while K m remained constant with K i equal to 84.2 ±5.1 µM, indicating a non‐competitive mechanism of inhibition. However, LC‐MS/MS analysis showed that FAAH is hydrolyzed 92 % of NPMO in a 60 minute of reaction, indicating that NPMO is also a substrate for FAAH. These results provide valuable information regarding macamide analogs and derivatives as FAAH inhibitors. NPMO could be used as a lead compound to design promising, selective, and potent FAAH inhibitors that could be used clinically as neuroprotectants targeting the endocannabinoid system.