NT69L: a potential, novel antischizophrenic drug

描述（由申请人提供）：研究一种新的神经紧张素（NT）肽类似物，称为NT69L，它可能是治疗精神分裂症的一类新药物的代表。这种化合物目前正在进行临床前毒理学测试，以便向美国食品和药物管理局申请新药，这样我们就可以在精神分裂症患者身上进行初步研究。迄今为止，NT69L在啮齿动物身上的实验，包括脉冲前抑制研究，强烈表明它将具有抗精神分裂症的作用。此外，初步的体内微透析研究表明，它还将具有增强认知的作用。我们假设NT69L在行为和生化作用上与氯氮平（一种经典的非典型抗精神病药物）相似。此外，我们假设氯氮平的一些行为影响是通过神经紧张素受体介导的（亚型1）。拟研究的具体目的是：1)确定单次注射和21次每日注射（亚慢性治疗）后，NT69L对药物性脉冲前抑制中断的逆转的起效和抵消的时间过程及其效果的剂量反应；2)比较典型抗精神病药物氟哌啶醇和非典型抗精神病药物氯氮平与NT69L在单次注射和每日注射21次后逆转药物性脉前抑制中断的效果；3)测定急性和亚慢性治疗时NT69L对蛋白表达的调节能力，并与每日注射1次氯氮平和21次注射氟哌啶醇对蛋白表达的影响进行比较；4)确定NT69L的几种行为效应的神经紧张素受体亚型特异性；6)确定氯氮平的某些行为效应是否需要NT受体亚型1。为了进行这些研究，我们将利用动物行为试验来预测抗精神病药物的疗效（例如，药物引起的脉冲前抑制的破坏）；蛋白质组学研究的先进方法；靶向神经紧张素受体1和2亚型的反义肽核酸和缺乏神经紧张素受体（亚型1或亚型2）的敲除小鼠。

DESCRIPTION (provided by applicant): Studies are proposed on a novel peptide anaolog of neurotensin (NT), called NT69L, which may be representative of a new class of drugs for treatment of schizophrenia. This compound is presently in preclinical toxicology testing for an Investigational New Drug application to the U.S. Food and Drug Administration so that we can do a pilot study in schizophrenic patients. Experiments to date on NT69L in rodents animals, including prepulse inhibition studies, strongly suggest that it will have antischizophrenic effects. In addition, preliminary in vivo microdialysis studies, suggest that it will also have cognitive- enhancing effects. We are hypothesizing that NT69L is similar in its behavioral and in its biochemical effects to clozapine, the classical, atypical antipsychotic drug. Additionally, we are hypothesizing that some of the behavioral effects of clozapine are mediated through neurotensin receptors (subtype 1). The Specific Aims of the proposed research are: 1) Determine the time course for the onset and offset of the reversal by NT69L of drug-induced disruption of prepulse inhibition and the dose-response for its effects, after a single injection and after 21 daily injections (subchronic treatment) of NT69L; 2) Compare the effects of the typical antipsychotic drug haloperidol and the atypical antipsychotic drug clozapine with those of NT69L on the reversal of drug-induced disruption of prepulse inhibition, after a single injection and after 21 daily injections of these antipsychotic drugs; 3) Determine the ability of NT69L to regulate protein expression with acute treatment and subchronic treatment and compare these effects on protein expression with those of clozapine and those of haloperidol, given once and after 21 daily injections; 4) Determine the neurotensin receptor subtype specificity of NT69L for several of its behavioral effects; 6) Determine whether some of clozapine's behavioral effects require NT receptors, subtype 1. To do these studies we will make use of animal behavioral tests predictive of antipsychotic efficacy (e.g., drug-induced disruption of prepulse inhibition); advanced methods of proteomics research; antisense peptide nucleic acids targeting neurotensin receptors, subtype 1 and 2; and knockout mice lacking neurotensin receptors (either subtype 1 or subtype 2).