NT69L: a potential, novel antischizophrenic drug

描述(申请人提供)：建议研究一种新的神经降压素(NT)多肽类似物，称为NT69L，它可能代表一类治疗精神分裂症的新药。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研究新药，以便我们可以在精神分裂症患者身上进行试点研究。迄今为止，在啮齿动物身上进行的NT69L实验，包括脉搏前抑制研究，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在其行为和生化效应上与氯氮平相似，氯氮平是一种经典的非典型抗精神病药物。此外，我们假设氯氮平的一些行为效应是通过神经降压素受体(亚型1)介导的。研究的具体目的是：1)确定NT69L单次注射和每天21次注射(亚慢性治疗)后，NT69L逆转药物引起的脉前抑制中断的开始和消失的时间进程及其效应的剂量反应；2)比较典型的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21次每日注射后逆转药物引起的脉前抑制中断的作用；3)确定NT69L在急性治疗和亚慢性治疗中调节蛋白质表达的能力，并将这些对蛋白质表达的影响与氯氮平和氟哌啶醇每日注射一次和21次后的影响进行比较；4)确定NT69L的几种行为效应的神经降压素受体亚型特异性；6)确定氯氮平的一些行为效应是否需要1亚型NT受体。为了做这些研究，我们将利用抗精神病药物疗效的动物行为预测试验(例如，药物诱导的前脉冲抑制中断)；蛋白质组学研究的先进方法；针对神经降压素受体、1和2亚型的反义多肽核酸；和缺乏神经降压素受体(亚型1或亚型2)的基因敲除小鼠。

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).