油酰胺衍生物的合成及催眠活性研究

【作者】 郭长彬；

【导师】 宋宏锐；

【作者基本信息】 沈阳药科大学 ， 药物化学， 2001， 硕士

【摘要】 油酰胺是油酸的伯酰胺，化学名为顺-9-十八碳烯酰胺，是近几年来发现的内源性睡眠诱导物质，合成的油酰胺对实验动物腹腔注射、脑腔注射或灌胃给药均可引起生理性睡眠。本文对睡眠生理和镇静催眠药的现状、油酰胺的催眠活性和其它生理作用及构效关系、生合成和代谢途径以及其催眠活性的可能作用机制进行了综述。 本文以油酰胺为先导化合物，设计并合成23个油酰胺衍生物（包括6个N-取代油酰胺衍生物和17个N-油酰-N’-取代哌嗪类衍生物），其中16个未见文献报道，并通过¹H—NMR、¹³C—NMR和IR确定了其化学结构。对小鼠催眠活性试验结果表明：与空白溶剂相比较，18个化合物具有显著的催眠活性；当腹腔注射给药时，油酰胺（S01）、N-乙基油酰胺（S02）、油酰哌嗪（S07）、1-油酰-4-乙基哌嗪（S10A）及其盐酸盐（S10B）五个化合物的催眠活性与地西泮相近，但是当灌胃给药时，其活性是地西泮的1/10～1/20；当腹腔注射给药时，S07的催眠活性超过先导化合物S01，但当灌胃给药时，两者的活性无显著性差异。对催眠活性的试验结果显示：油酰胺和油酰哌嗪的氮原子被烷基或芳基取代后，催眠活性均较母体化合物降低，同时给药刺激性也降低。更多还原

【Abstract】 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.更多还原