Can Amphipathic Helices Influence the CNS Antinociceptive Activity of Glycopeptides Related to β-Endorphin?
Can Amphipathic Helices Influence the CNS Antinociceptive Activity of Glycopeptides Related to β-Endorphin?
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DOI：
10.1021/jm400879w
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发表时间：
2014-03-27
影响因子：
7.3
通讯作者：
Polt, Robin
中科院分区：
文献类型：
--
作者：
Li, Yingxue;St Louis, Lindsay;Polt, Robin
在体外和小鼠体内研究了各种两亲性的糖基化β-内啡肽类似物。在CHO细胞中表达的人受体中测量O-连接糖肽（单糖或二糖）和未糖基化肽对照的阿片样物质结合亲和力。所有这些都是泛激动剂，在低纳摩尔范围（2.2-35 nM Ki）内与μ-、δ-或κ-阿片受体结合。静脉内（i. v.）但不用于脑室内（i. c. v.）活动三氟乙醇或胶束的圆二色性。糖基化对于静脉给药后的活性至关重要。通过改变β-内啡肽类似物的螺旋地址区域中的仅两个氨基酸残基来操纵螺旋度是可能的，而不破坏μ-、δ-或κ-激动作用，但是静脉内给药后的抗伤害感受活性不能与胶束中的螺旋度直接相关。
Glycosylated beta-endorphin analogues of various amphipathicity were studied in vitro and in vivo in mice. Opioid binding affinities of the O-linked glycopeptides (mono- or disaccharides) and unglycosylated peptide controls were measured in human receptors expressed in CHO cells. All were pan-agonists, binding to mu-, delta-, or kappa-opioid receptors in the low nanomolar range (2.2-35 nM K-i's). The glycoside moiety was required for intravenous (i.v.) but not for intracerebroventricular (i.c.v.) activity. Circular dichroism trifluoroethanol, or micelles. Glycosylation was essential for activity after i.v. administration. It was possible to manipulate the degree of helicity by the alteration of only two amino acid residues in the helical address region of the beta-endorphin analogues without destroying mu-, delta-, or kappa-agonism, but the antinociceptive activity after i.v. administration could not be directly correlated to the degree of helicity in micelles.