In vivo behavioral effects of stable, receptor-selective neurotensin[8-13] analogues that cross the blood-brain barrier.
In vivo behavioral effects of stable, receptor-selective neurotensin[8-13] analogues that cross the blood-brain barrier.
复制标题
穿过血脑屏障的稳定的受体选择性神经降压素[8-13]类似物的体内行为效应。
DOI：
10.1016/j.neuropharm.2004.10.008
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发表时间：
2005
期刊：
影响因子：
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通讯作者：
Dix,ThomasA
中科院分区：
文献类型：
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作者：
Kokko,KyleP;Hadden,MKyle;Price,KimberL;Orwig,KevinS;See,RonaldE;Dix,ThomasA
一组神经紧张素[8-13]（NT[8-13]）类似物（KK1-19）已经在各种临床前试验中进行了评估，这些试验与进一步开发这些化合物作为潜在的抗精神病药物有关。对这些化合物进行初步筛选，以诱导大鼠全身静脉注射后的低温，这是一种通常用于测量NT类似物中枢神经系统（CNS）活性的间接方法[8-13]，鉴定出三种肽，KK1， KK13和KK14，能够穿过血脑屏障（BBB）。KK1在Arg(8)位置具有2(S)-叠氮-7-氨基庚酸（AAHA），是第一个单取代NT[8 - 13]类似物穿过血脑屏障。KK13和KK14在Arg(8)位置上都含有AAHA，在Ile（12）位置上含有tert-Leu，而KK14在Tyr（11）位置上含有Trp。当使用ipp时，只有后两种类似物引起明显的低体温反应。KK13 （1mg/kg）可抑制苯丙胺类药物诱导的过度运动；该试验对潜在的抗精神病药物具有高度预测性。长期给药（5mg/kg）连续5天不能诱导低温耐受性，而相同剂量不能诱导可测量的猝厥。因此，KK13是迄今为止描述的第一个NT[8-13]类似物，它可以抑制安非他明引起的过度运动而不引起猝厥，同时维持日常的低温效力。
A set of neurotensin[8–13] (NT[8–13]) analogues (KK1–19) has been evaluated in various pre-clinical assays relevant for further development of these compounds as potential antipsychotics. Initial screening of these compounds for induction of hypothermia following systemic (I.V.) injection in rats, an indirect method commonly utilized to measure the central nervous system (CNS) activity of NT[8–13] analogues, identified three peptides, KK1, KK13 and KK14, capable of crossing the blood–brain barrier (BBB). KK1 features 2(S)-azido-7-aminoheptanoic acid (AAHA) in the Arg(8) position and represents the first monosubstituted NT[8–13] analogue that crosses the BBB. KK13 and KK14 both feature AAHA in the Arg(8) position and tert-Leu in the Ile(12) position while KK14 includes a Trp substituted for Tyr(11). When I.P. administered, only the latter two analogues induced a significant hypothermic response. KK13 (1mg/kg) inhibited amphetamine-induced hyperlocomotion after I.P. injection; this assay is highly predictive for potential antipsychotics. Chronic dosing (5mg/kg) of this compound over 5 consecutive days failed to induce hypothermic tolerance while the same dose failed to induce measurable catalepsy. KK13 is thus the first NT[8–13] analogue described to date that demonstrates inhibition of amphetamine-induced hyperlocomotion without inducing catalepsy while maintaining day-to-day hypothermic potency.