Delineation of a Fundamental α-Ketoheterocycle Substituent Effect for Use in the Design of Enzyme Inhibitors

摘要

Anandamide (1a) and oleamide (1b) have emerged as the prototypical members of a class of endogenous fatty acid amides that serve as chemical messengers (Figure 1). Anandamide binds and activates the central (CB1) and peripheral (CB2) cannabinoid receptors where it has been implicated in the modulation of nociception, feeding, and anxiety. Oleamide was found to accumulate in the cerebrospinal fluid of animals under conditions of sleep deprivation and induces physiological sleep in a dose-dependent manner. The pharmacological action of both anandamide and oleamide is terminated by the enzyme fatty acid amide hydrolase (FAAH, Figure 1). It degrades neuromodulating fatty acid amides at their site of action and is currently the only characterized mammalian enzyme that is in the amidase signature family bearing an unusual catalytic Ser-Ser-Lys triad. As such, FAAH has emerged as an exciting therapeutic target for a range of clinical disorders.