Agonists at cannabinoid receptors, such as the phytocannabinoid Δ(9)-tetrahydrocannabinol, exert a remarkable array of therapeutic effects but are also associated with undesirable psychoactive side effects. Conversely, targeting enzymes that hydrolyze endocannabinoids (eCBs) allows for more precise fine-tuning of cannabinoid receptor signaling, thus providing therapeutic relief with reduced sid...

Organophosphorus (OP) and thiocarbamate (TC) agrochemicals are used worldwide as insecticides, herbicides, and fungicides, but their safety assessment in terms of potential off-targets remains incomplete. In this study, a chemoproteomic platform, termed activity-based protein profiling, was used to broadly define serine hydrolase targets in mouse brain of a panel of 29 OP and TC pesticides. Amo...

The concurrent implementation of a proteome-wide serine hydrolase selectivity screen with traditional efforts to optimize fatty acid amide hydrolase (FAAH) inhibition potency led to the expedited discovery of a new class of exceptionally potent (Ki < 300 pM) and unusually selective (> 100-fold selective) inhibitors. The iterative inhibitor design and evaluation with assistance of the selectivit...

Endogenous ligands for cannabinoid receptors ("endocannabinoids") include the lipid transmitters anandamide and 2-arachidonoylglycerol (2-AG). Endocannabinoids modulate a diverse set of physiological processes and are tightly regulated by enzymatic biosynthesis and degradation. Termination of anandamide signaling by fatty acid amide hydrolase (FAAH) is well characterized, but less is known abou...

Fatty acid ethanolamides (FAEs) and endocannabinoids (ECs) have been shown to alleviate pain and inflammation, regulate motility and appetite, and produce anticancer, anxiolytic, and neuroprotective efficacies via cannabinoid receptor type 1 (CB1) or type 2 (CB2) or via peroxisome proliferator-activated receptor α (PPAR-α) stimulation. FAEs and ECs are synthesized by a series of endogenous enzy...

The methanolic fruit extract of Tetrapleura tetraptera was analyzed for the presence phytocompounds, their bioactivity, functional groups involved in this activity, and its amino acid profile using standard procedures. Phytochemicals such as tannins, phenols, flavonoids, alkaloids were identified being highly present. Gas chromatographic-mass spectrometric (GC-MS) analysis 16 bioactive compound...

Fatty acid amide hydrolase (FAAH) is a promising target for the development of drugs to treat neurological diseases. In search of new FAAH inhibitors, we identified 2-(4-cyclohexylphenoxy)-N-(3-(oxazolo[4,5-b]pyridin-2-yl)phenyl)acetamide, 4g, with an IC50 of 2.6 µM as a chemical starting point for the development of potent FAAH inhibitors. Preliminary hit-to-lead optimisation resulted in 2-(4-...

words) : 230 Introduction (words) : 861 Discussion (words) : 653 Non-standard abbreviations: DSE, depolarization induced suppression of excitation; 2-AG, 2-arachidonoyl glycerol; FAAH, fatty acid amide hydrolase; COX-2, cyclooxygenase-2; MGL, monoacyl glycerol lipase; ABHD6/12, α/βhydrolase domain 6 and 12; AEA, arachidonoyl ethanolamide; MAFP, methyl arachidonoyl fluorophosphonate; NAM, N-arac...

Allergic contact dermatitis affects about 5% of men and 11% of women in industrialized countries and is one of the leading causes for occupational diseases. In an animal model for cutaneous contact hypersensitivity, we show that mice lacking both known cannabinoid receptors display exacerbated allergic inflammation. In contrast, fatty acid amide hydrolase-deficient mice, which have increased le...