NT69L: a potential, novel antischizophrenic drug

NT69L：一种潜在的新型抗精神分裂症药物

基本信息

批准号：
7409750
负责人：
ELLIOTT RICHELSON
金额：
$ 28.23万
依托单位：
MAYO CLINIC JACKSONVILLE
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-05-15 至 2010-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7409750
关键词：
Acute Agonist Amphetamines Animals Antipsychotic Agents Apomorphine Applications Grants Behavior Behavioral Biochemical Brain Class Clozapine Cocaine Cognitive Daily Data Disruption Dose Generations Haloperidol Injection of therapeutic agent Investigational New Drug Application Knockout Mice Laboratory Animals Mediating Methods Microdialysis Mus NMDA receptor antagonist Neuropeptide Receptor Neurotensin Neurotensin Receptors Nicotine Nicotine Dependence Nylons Patients Peptide Hydrolases Peptide Nucleic Acids Peptides Pharmaceutical Preparations Pilot Projects Prevalence Proteomics Rattus Research Research Personnel Rodent Schizophrenia Serotonin Specificity Testing Thinking Time Toxicology United States Food and Drug Administration antischizophrenic atypical antipsychotic behavior test cigarette smoking clinical effect dizocilpine in vivo neurotensin 69L novel pre-clinical prepulse inhibition programs protein expression psychostimulant receptor research study response

项目摘要

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).

描述（由申请人提供）：提出了关于神经降压素（NT）的新型肽类似物（NT69L）的研究，它可能是治疗精神分裂症的一类新药物的代表。该化合物目前正在向美国食品和药物管理局申请新药研究申请的临床前毒理学测试，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身上进行的 NT69L 实验，包括前脉冲抑制研究，强烈表明它具有抗精神分裂症作用。此外，初步的体内微透析研究表明，它还具有增强认知的作用。我们假设 NT69L 的行为和生化作用与经典的非典型抗精神病药物氯氮平相似。此外，我们假设氯氮平的一些行为效应是通过神经降压素受体（1 亚型）介导的。拟议研究的具体目标是： 1) 确定 NT69L 逆转药物诱导的前脉冲抑制破坏的发生和抵消的时间过程，以及单次注射后和每天 21 日后其效果的剂量反应NT69L注射（亚慢性治疗）； 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 21 次注射后对药物引起的前脉冲抑制破坏的逆转作用； 3) 确定NT69L在急性治疗和亚慢性治疗中调节蛋白表达的能力，并将这些对蛋白表达的影响与氯氮平和氟哌啶醇（每天注射一次和21天注射后）进行比较； 4) 确定NT69L的神经降压素受体亚型特异性对其几种行为效应的影响； 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测试来预测抗精神病药的功效（例如，药物诱导的前脉冲抑制破坏）；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）的基因敲除小鼠。