Enkephalin glycopeptide analogues produce analgesia with reduced dependence liability
Enkephalin glycopeptide analogues produce analgesia with reduced dependence liability
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DOI：
10.1021/jm000077y
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发表时间：
2000-06-29
影响因子：
7.3
通讯作者：
Polt, R
中科院分区：
文献类型：
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作者：
Bilsky, EJ;Egleton, RD;Polt, R
内源性肽（例如脑啡肽）控制大脑功能、认知和感知的许多方面。这些神经活性肽在各种研究中的使用增加了对大脑功能的理解。不幸的是，使用脑源性肽作为药剂来改变体内脑化学已经滞后，因为肽不容易穿透血脑屏障。单糖与脑啡肽的连接增加了它们对血脑屏障的渗透，并允许所得的糖肽类似物有效地发挥药物的作用。δ-选择性糖基化亮氨酸-脑啡肽酰胺2，H2 N-Tyr-D-Thr-Gly-Phe-Leu-Ser（β-D-Glc）-CONH 2，即使在外周给药时也能产生类似于吗啡的镇痛作用，但依赖性降低，如纳洛酮促戒断研究所示。类似的基于糖肽的药物提出了缓解疼痛的承诺，其副作用特征优于目前可用的阿片类镇痛药。
Endogenous peptides (e.g. enkephalins) control many aspects of brain function, cognition, and perception. The use of these neuroactive peptides in diverse studies has led to an increased understanding of brain function. Unfortunately, the use of brain-derived peptides as pharmaceutical agents to alter brain chemistry in vivo has lagged because peptides do not readily penetrate the blood-brain barrier. Attachment of simple sugars to enkephalins increases their penetration of the blood-brain barrier and allows the resulting glycopeptide analogues to function effectively as drugs. The delta-selective glycosylated Leu-enkephalin amide 2, H2N-Tyr-D-Thr-Gly-Phe-Leu-Ser(beta-D-Glc)-CONH2, produces analgesic effects similar to morphine, even when administered peripherally, yet possesses reduced dependence liability as indicated by naloxone-precipitated withdrawal studies. Similar glycopeptide-based pharmaceuticals hold forth the promise of pain relief with improved side-effect profiles over currently available opioid analgesics.