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：
7595117
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/7595117
关键词：
Acute Agonist Amphetamines Animals Antipsychotic Agents Apomorphine Applications Grants Behavior Behavioral Biochemical Brain Clozapine Cocaine Cognitive Data 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 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）：对一种称为NT69L的新型肽（NT）进行了研究，该研究可能代表了一种用于治疗精神分裂症的新药物。目前，该化合物用于临床前毒理学测试，用于对美国食品药品监督管理局进行研究的新药应用，因此我们可以在精神分裂症患者中进行试点研究。迄今为止，在啮齿动物的NT69L上进行的实验，包括预硫抑制作用，强烈表明它将具有抗消毒作用。此外，初步体内微透析研究表明，它也将具有认知增强的效果。我们假设NT69L的行为和生化作用与氯氮平是经典的非典型抗精神病药。此外，我们假设氯氮平的某些行为作用是通过神经素受体介导的（亚型1）。拟议研究的具体目的是：1）确定NT69L药物诱导的预硫抑制的破坏和剂量反应的逆转的时间过程，并在单次注射后和21个每日注射（下21个注射剂（亚chronic治疗））的剂量响应； 2）将典型的抗精神病药氟哌啶醇和非典型抗精神病药氯氮平与NT69L的典型抗精神病药物的作用与单一注射后的药物诱导的抑制作用的逆转以及这些抗精神病药的每日注射后，对药物诱导的抑制作用的逆转； 3）确定NT69L通过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作用与氯氮平和氟哌啶醇的蛋白质表达进行比较，每天21次注射一次； 4）确定NT69L的神经素受体亚型特异性对其几种行为效应； 6）确定氯氮平的某些行为效应是否需要NT受体，亚型1。要进行这些研究，我们将利用可预测抗精神病药疗效的动物行为测试（例如，药物诱导的预硫抑制作用破坏）；蛋白质组学研究的先进方法；靶向神经素受体的反义肽核酸，亚型1和2；和缺乏神经素受体的敲除小鼠（亚型1或亚型2）。

项目成果

期刊论文数量（8）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The role of NTS2 in the development of tolerance to NT69L in mouse models for hypothermia and thermal analgesia.

NTS2 在低温和热镇痛小鼠模型中 NT69L 耐受性发展中的作用。

DOI：
10.1016/j.bbr.2011.06.014
发表时间：
2011
期刊：
Behavioural brain research
影响因子：
2.7
作者：
Smith,KristinE;Boules,Mona;Williams,Katrina;Fauq,AbdulH;Richelson,Elliott
通讯作者：
Richelson,Elliott

Chronic NT69L potently prevents drug-induced disruption of prepulse inhibition without causing tolerance.

DOI：
10.1016/j.bbr.2009.09.044
发表时间：
2010-02-11
期刊：
BEHAVIOURAL BRAIN RESEARCH
影响因子：
2.7
作者：
Briody, Siobhan;Boules, Mona;Oliveros, Alfredo;Fauq, Irfan;Richelson, Elliott
通讯作者：
Richelson, Elliott

DOI：
10.1016/j.nbd.2010.07.011
发表时间：
2010-11
期刊：
Neurobiology of disease
影响因子：
6.1
作者：
Li Z;Boules M;Williams K;Gordillo A;Li S;Richelson E
通讯作者：
Richelson E

NT79: A novel neurotensin analog with selective behavioral effects.

DOI：
10.1016/j.brainres.2009.10.050
发表时间：
2010-01-13
期刊：
BRAIN RESEARCH
影响因子：
2.9
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
通讯作者：
Richelson, Elliott

Hyperactivity of the dopaminergic system in NTS1 and NTS2 null mice.

DOI：
10.1016/j.neuropharm.2010.02.015
发表时间：
2010-06
期刊：
NEUROPHARMACOLOGY
影响因子：
4.7
作者：
Liang, Yanqi;Boules, Mona;Li, Zhimin;Williams, Katrina;Miura, Tomofumi;Oliveros, Alfredo;Richelson, Elliott
通讯作者：
Richelson, Elliott