The endocannabinoid system comprises the two well characterized Gi/o -protein coupled receptors (cannabinoid receptor 1 (CB1) and CB2), their endogenous lipid ligands, and the enzymes involved in their biosynthesis and biotransformation. Drug discovery efforts relating to the endocannabinoid system have been focused mainly on the two cannabinoid receptors and the two endocannabinoid deactivatin...

The X-ray crystal structures of five distinct enzymes (prostaglandin H(2) synthase, squalene cyclase, fatty acid amide hydrolase, microsomal cytochrome P450, and estrone sulfatase) challenge contemporary descriptions of integral membrane proteins. This structurally divergent group represents an important component of the integral membrane proteome that lies at the bilayer's aqueous interface. W...

Anandamide (AEA) impairs mouse pregnancy and embryo development. Here, we overview the role of AEA in sexual function, focusing on AEA degradation during human pregnancy. Human peripheral lymphocytes express the AEA-hydrolyzing enzyme fatty acid amide hydrolase (FAAH), which decreases in miscarrying women. FAAH is regulated by progesterone and Th1/Th2 cytokines, whereas the AEA transporter and ...

FAAH (fatty acid amide hydrolase) is a promising target for the treatment of several central nervous system and peripheral disorders. Combined QM/MM (quantum mechanics/molecular mechanics) calculations have elucidated the role of its unusual catalytic triad in the hydrolysis of oleamide and oleoylmethyl ester substrates, and have identified the productive inhibitor-binding orientation for the c...

Multi-target inhibitors have become increasing popular as a means to leverage the advantages of poly-pharmacology while simplifying drug delivery. Here, we describe dual inhibitors for soluble epoxide hydrolase (sEH) and fatty acid amide hydrolase (FAAH), two targets known to synergize when treating inflammatory and neuropathic pain. The structure activity relationship (SAR) study described her...

New analogs of amino acid-conjugated bile acids were synthesized in which the amide bond was reversed from its normal configuration. These structural isomers of the beta-alanyl conjugates of cholic acid and ursodeoxycholic acid were synthesized by reaction of succinic anhydride with the 24-nor-23-amine derivatives of cholic acid and ursodeoxycholic acid. The chemical and physical properties of ...