Synthesis and in vitro evaluation of lipoamino acid and carbohydrate-modified enkephalins as potential antinociceptive agents

被引:43
作者
Kellam, B
Drouillat, B
Dekany, G
Starr, MS
Toth, I
机构
[1] Univ London, Sch Pharm, Dept Pharmaceut & Biol Chem, London WC1N 1AX, England
[2] Univ London, Sch Pharm, Dept Pharmacol, London WC1N 1AX, England
基金
英国惠康基金;
关键词
blood-brain barrier; drug delivery; enkephalins; solid-phase peptide synthesis; lipoamino acids; glycopeptides;
D O I
10.1016/S0378-5173(97)00328-1
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
The principal hindrance to drug uptake into central nervous tissue is the blood-brain barrier (BBB). In addition, potential peptide-based neuropharmaceuticals are rapidly destroyed by intra-and extracellular peptidases. In an attempt to address these biological hurdles, a series of lipo-, glyco- and glycolipo-conjugates of Leu-enkephalin have been synthesised via novel solid-phase strategies, and their in vitro activity assessed using mouse vas deferens (MVD) and guinea pig ileum (GPI) assays. Conjugation of a single lipoamino acid onto the C-terminal of the Leu-enkephalin molecule retains biological activity whilst increasing the molecule's overall lipophilicity. Conjugation of a glucuronic acid analogue in an analogous position, however, increases activity 40-fold when compared to the native peptide and induces a high degree of delta-opioid receptor selectivity. (C) 1998 Elsevier Science B.V.
引用
收藏
页码:55 / 64
页数:10
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