INHIBITION OF OLEAMIDE HYDROLASE CATALYZED-HYDROLYSIS OF THE ENDOGENOUS SLEEP-INDUCING LIPID CIS-9-OCTADECENAMIDE

Oleamide (1, cis-9-octadecenamide) is a naturally occurring brain cons tituent that. has been shown to accumulate and disappear under conditi ons of sleep deprivation and sleep recovery, respectively. Synthetic 1 has been found to induce sleep in a structurally specific manner at n anomolar quantities. Hydrolysis of 1 by an enzyme (oleamide hydrolase) present in the cell membrane rapidly degrades oleamide to oleic acid (cis-9-octadecenoic acid). Such observations suggest 1 may constitute a prototypical member of a class of fatty acid primary amide biologica l signaling molecules in which the diversity and selectivity of functi on are derived from the length of the alkane chain as well as the posi tion, stereochemistry, and degree of unsaturation. A series of inhibit ors of oleamide hydrolase were designed and prepared which were expect ed to derive their properties through interactions with the putative a ctive site cysteine residue within oleamide hydrolase. This approach y ielded a series of rapid, selective, and highly potent inhibitors (K-i = 13 mu M to 1 nM) which in addition to their potential therapeutic v alue may serve as useful tools to define the biological role of oleami de.