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首页> 外文期刊>Proceedings of the National Academy of Sciences of the United States of America >Zyklophin, a systemically active selective kappa opioid receptor peptide antagonist with short duration of action
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Zyklophin, a systemically active selective kappa opioid receptor peptide antagonist with short duration of action

机译：Zyklophin，一种具有短暂作用时间的全身活性选择性κ阿片受体肽拮抗剂

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The cyclic peptide zyklophin {[N-benzylTyr~1,cyclo(D-Asp~5,Dap~8)-dynorphin A-(1-11)NH_2, Patkar KA, et al. (2005) J Med Chem 48: 4500-4503} is a selective peptide kappa opioid receptor (KOR) antagonist that shows activity following systemic administration. Systemic (1-3 mg/kg s.c.) as well as central (0.3-3 nmol intracerebro-ventricular, i.c.v.) administration of this peptide dose-dependently antagonizes the antinociception induced by the selective KOR agonist U50,488 in C57BL/6J mice tested in the 55℃ warm water tail withdrawal assay. Zyklophin administration had no effect on morphine- or SNC-80-mediated antinociception, suggesting that zyklophin selectively antagonizes KOR in vivo. Additionally, the antagonism of antinociception induced by centrally (i.c.v.) administered U50,488 following peripheral administration of zyklophin strongly suggests that the peptide crosses the blood-brain barrier to antagonize KOR in the CNS. Most importantly, the antagonist activity of zyklophin (3 mg/kg s.c.) lasts less than 12 h, which contrasts sharply with the exceptionally long duration of antagonism reported for the established small-molecule selective KOR antagonists such as nor-binaltorphimine (nor-BNI) that last weeks after a single administration. Systemically administered zyklophin (3 mg/kg s.c.) also prevented stress-induced reinstatement of cocaine-seeking behavior in a conditioned place preference assay. In conclusion, the peptide zyklophin is a KOR-selective antagonist that exhibits the desired shorter duration of action, and represents a significant advance in the development of KOR-selective antagonists.
机译：环肽zyklophin {[N-苄基Tyr-1，环（D-Asp-5，Dap-8）-强啡肽A-（1-11）NH_2，Patkar KA等。 （2005）J Med Chem 48：4500-4503}是一种选择性肽κ阿片受体（KOR）拮抗剂，其在全身给药后显示活性。对该肽的全身性（1-3 mg / kg sc）以及中央（0.3-3 nmol脑室内，icv）剂量依赖性地拮抗选择性KOR激动剂U50,488在测试的C57BL / 6J小鼠中诱导的抗伤害感受在55℃温水尾巴抽提法中进行。吡咯烷酮的施用对吗啡或SNC-80介导的镇痛作用没有影响，这表明吡咯烷酮在体内选择性拮抗KOR。另外，由zyklophin的外围给药后，通过集中（i.c.v.）给药U50,488诱导的抗伤害感受的拮抗作用强烈表明，该肽穿过血脑屏障以拮抗CNS中的KOR。最重要的是，zyklophin（3 mg / kg sc）的拮抗剂活性持续不到12小时，这与已报道的已确立的小分子选择性KOR拮抗剂（如去甲双鸟嘌呤（nor-BNI）的拮抗作用持续时间长短形成鲜明对比） ），即单次给药后的最后几周在条件性位置偏爱试验中，全身施用zyklophin（3 mg / kg s.c.）还可以预防应激诱导的可卡因寻觅行为的恢复。总之，肽zyklophin是一种KOR-选择性拮抗剂，具有所需的较短作用时间，代表了KOR-选择性拮抗剂的发展中的重要进展。

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