Oil Amide Derivatives And Hypnotic Activity

Oleaniide is the primary amide of oleic acid and its chemical name is cis-9-octadecenoamide. Oleamide is an endogenous sleep-inducing substance that was found in recent years to accumulate in the cerebrospinal fluid of mammals under conditions of sleep deprivation and to induce physiological sleep in laboratory animals by injected with synthetic oleamide intraperitoneally, intraventricularly or per os. In this paper, sleep physiology, present status of sedative and hypnotics, the hypnotic and other physiological activities and structure-activity relationships (SAR), mechanisms of sleep inducing, biosynthesis and metabolism of oleamide are reviewed. With oleamide as a lead compound, 23 oleamide derivatives were designed and synthesized , consisting of 6 N-substituted oleamide derivatives and 17 N-oleoyl-N?-substituted piperazine derivatives, among which 16 compounds have not been reported in literature, and their structures were identified by -NMR , 13C-NMR , and IR. Pharmacological studies showed that 18 compounds have significant hypnotic activities on mice when compared with solvent; the hypnotic activities of compounds S01, S02, S07, S1OA and its hydrochloride salt SlOB are comparable to that of Diazepam when administrated intraperitoneally, but they are only 1/10?/20 of that of Diazepam when administrated per os; the hypnotic activity of N-oleoyl piperazine(S07) is higher than that of oleamide(S01) when administrated intraperitoneally , but it has no significant difference with the latter when administrated per os. Preliminary studies on SAR of hypnotic activity revealed that the hypnotic activities and irritations of N-substituted oleamide derivatives and N-oleoyl-N?-substituted piperazine derivatives are both lower than those of their mother substances S01 and S07.