NT69L: a potential, novel antischizophrenic drug

描述（由申请人提供）：提出了对神经降压素（NT）的新型肽类似物（称为NT 69 L）的研究，其可能是治疗精神分裂症的一类新药的代表。这种化合物目前正在进行临床前毒理学测试，用于向美国食品和药物管理局申请研究性新药，以便我们可以在精神分裂症患者中进行试点研究。迄今为止在啮齿动物中对NT 69 L的实验，包括前脉冲抑制研究，强烈表明它将具有抗精神分裂症作用。此外，初步的体内微透析研究表明，它也将具有认知增强作用。我们假设NT 69 L在行为和生化作用上与经典的非典型抗精神病药物氯氮平相似。此外，我们假设氯氮平的某些行为效应是通过神经降压素受体（亚型1）介导的。拟进行的研究的具体目的是：1）确定单次注射和21次每日注射后NT 69 L对药物诱导的前脉冲抑制破坏的逆转的开始和抵消的时间过程及其效应的剂量反应（亚慢性治疗）NT 69 L; 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NT 69 L对药物引起的前脉冲抑制破坏的逆转作用，3）测定NT 69 L用急性治疗和亚慢性治疗调节蛋白质表达的能力，并将这些对蛋白质表达的影响与每天注射一次和21次后给予的氯氮平和氟哌啶醇的影响进行比较; 4）确定NT 69 L的神经降压素受体亚型特异性，用于其几种行为效应; 6）确定氯氮平的一些行为效应是否需要NT受体亚型1。为了进行这些研究，我们将利用预测抗精神病疗效的动物行为测试（例如，前脉冲抑制的药物诱导的破坏）;蛋白质组学研究的先进方法;靶向神经降压素受体亚型1和2的反义肽核酸;以及缺乏神经降压素受体（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).