NT79: A novel neurotensin analog with selective behavioral effects.
NT79: A novel neurotensin analog with selective behavioral effects.
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NT79：一种具有选择性行为效应的新型神经素类似物。
DOI：
10.1016/j.brainres.2009.10.050
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发表时间：
2010-01-13
期刊：
影响因子：
2.9
通讯作者：
Richelson, Elliott
中科院分区：
文献类型：
--
作者：
Boules, Mona;Liang, Yanqi;Briody, Siobhan;Miura, Tomofumi;Fauq, Irfan;Oliveros, Alfredo;Wilson, Mina;Khaniyev, Shaheen;Williams, Katrina;Li, Zhimin;Qi, Yanfei;Katovich, Michael;Richelson, Elliott
神经降压素是一种十三肽，广泛分布于大脑和胃肠道。它具有止痛、降温和抗精神病药物样的特性。神经降压素的作用主要通过NTS1和NTS2两种受体亚型介导。NTS1的激活与神经降压素的大部分药理作用有关，但与体温过低和低血压有关。我们报道了一种新的神经降压素类似物，它对NTS2具有更高的选择性，即NT79，它具有选择性行为效应。NT79在疼痛的动物模型(热板试验；内脏醋酸诱导的扭体试验)和预测抗精神病药物样效应的动物模型(阿朴吗啡诱导的攀登；D-苯丙胺诱导的多动；脉冲前抑制的中断)中进行了测试。并测定了其对体温和血压的影响。用体内微透析法检测细胞外神经递质的神经化学变化，同时评估在使用和不使用NT79预处理的情况下大鼠的醋酸扭体反应。分子克隆的hNTS1和hNTS2的结合数据表明hNTS2具有选择性。NT79能拮抗冰醋酸引起的小鼠扭体反应，ED50为0.14μg/kg，但对热伤害性反应无明显影响。扭体反应与5-羟色胺的升高平行，而5-羟色胺的升高可被NT79减弱。NT79通过阻断阿朴吗啡引起的爬升、d-苯丙胺引起的多动，以及减少d-苯丙胺和DOI引起的脉冲前抑制的中断，显示出抗精神病药物的作用。独一无二的是，它没有引起明显的体温过低，对血压也没有影响。NT79对NTS2具有较高的选择性，可能用于治疗内脏疼痛和精神病，而不会伴随低温或低血压的副作用。
Neurotensin, a tridecapeptide, is widely distributed in the brain and gastrointestinal tract. It possesses analgesic, hypothermic, and antipsychotic-like properties. Neurotensin’s effects are mediated mainly through two receptor subtypes, NTS1 and NTS2. Activation of NTS1 has been implicated in most of the pharmacological effects of neurotensin, but is associated with hypothermia and hypotension. We report on a novel neurotensin analog with higher selectivity to NTS2, namely, NT79 which exhibits selective behavioral effects. NT79 was tested in animal models for pain (thermal - hot plate test; visceral – acetic acid-induced writhing test), and in animal models that are predictive of antipsychotic-like effects (apomorphine-induced climbing; d-amphetamine-induced hyperactivity; disruption of prepulse inhibition). Its effects on body temperature and on blood pressure were also determined. Neurochemical changes in extracellular neurotransmitters were measured using in vivo microdialysis while the rats were simultaneously evaluated for acetic acid-induced writhing with and without pretreatment with NT79. Binding data at molecularly-cloned hNTS1 and hNTS2 suggest selectivity for hNTS2. NT79 blocked the acetic acid-induced writhing with an ED50 of 0.14μg/kg, while having no effect on thermal nociception. The writhing was paralleled by an increase in 5-HT which was attenuated by NT79. NT79 demonstrated antipsychotic-like effects by blocking apomorphine-induced climbing, d-amphetamine-induced hyperactivity, and reducing d-amphetamine- and DOI-induced disruption of prepulse inhibition. Uniquely, it caused no significant hypothermia and was without effect on blood pressure. NT79, with its higher selectivity to NTS2, may be potentially useful to treat visceral pain, and psychosis without concomitant side effects of hypothermia or hypotension.
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