文档介绍：安徽中医学院
硕士学位论文
LPK-26对人κ阿片受体的调节作用及其作用机制的研究
姓名:张从芬
申请学位级别:硕士
专业:中药学
指导教师:彭代银
20060401
ACTCM2006 届硕士研究生论文:LPK-26 对人? 1 阿片受体的调节作用及其作用机制的研究
中文摘要
阿片类药物是临床上广泛应用的镇痛药物。但因其耐受性和成
瘾性等副作用限制了其临床疗效。以前的研究认为阿片类药物主要
是通过? 阿片受体发挥作用。但近年来研究发现?阿片受体激动剂的
作用不同于? 阿片受体激动剂。它不仅具有强效的镇痛作用,而且成
瘾性比? 阿片受体激动剂如吗啡较低。LPK-26 是以? 阿片受体激动剂
ICI-199441 为模板合成的一种新型的阿片配基。已有结果表明 LPK-
26 对小鼠具有强效的镇痛作用。本研究结果表明:LPK-26 对? 阿片
受体有较高的亲和力,其 Ki 值是 ,与 U50,488H 相似;并且
通过[35S]GTP?S 结合实验,LPK-26 激活 G 蛋白的能力明显大于
U50,488H;LPK-26 慢性处理 CHO/? OR 也可对? 阿片受体产生脱敏
和下调,其脱敏和受体下调程度比 U50,488H 较强;另一方面,LPK-26
慢性处理 CHO/? OR 细胞然后用 Naloxone 戒断,cAMP 超射水平显
著低于 U50,488H。结果表明:LPK-26 可能是一种较为理想的新型
镇痛药物。
关键词:CHO/?OR;受体脱敏;受体下调;cAMP 超射
ACTCM2006 届硕士研究生论文:LPK-26 对人? 1 阿片受体的调节作用及其作用机制的研究
Abstract
Opioid drugs are widely used as analgesics, but the clinic uses of them are limited
by their adverse side effects such as tolerance and dependence. ? –opioid receptor
agonists have been demonstrated to be different from µ–opioid receptor agonists, which
may provide a potent analgesic effect but have less abuse potential and the aversive
effects of µ–opioid receptor agonists like morphine. LPK-26 is pound synthesized
with ?–opioid receptor agonist, ICI-199441 as a template and introduction of 3-pyrroline
instead of conventional pyrrolidine substituent into the ?–pharmacophoric
ethylenediamine framework. It has been reported to have a potent analgesic effect in mice.
In this study, we demonstrated that LPK-26 was a highly selective ? –opioid receptor
agonist, displaying a high affinity for ? –opioid receptors with ki value of nM.
Although the Ki value of LPK-26 is similar to that of U50, 488H, LPK-26 exhibited a
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greater ability to stimulate [ S]GTP?S binding to membranes relative to U50, 488H.
Prolonged exposure of CHOKOR cells to LPK-26 and U50, 488H both led to a
pronounced desensitization and down-regulation of ? –opioid receptors, but, the extent of
desensitization and down-regulation by LPK-26 was h