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Novel Ligands that Selectively Desensitize alpha4beta nAChRs for Smoking Cessatio

选择性使 α4β nAChR 脱敏以戒烟的新型配体

基本信息

批准号：
8616367
负责人：
KENNETH J KELLAR
金额：
$ 84.33万
依托单位：
GEORGETOWN UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-03-15 至 2016-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8616367
关键词：
Acetylcholine Acute Adult Adverse effects Affect Affinity Agonist Americas Animals Antidepressive Agents Area Autopsy Back Behavior Binding Blood Brain Brain Stem Breathing Bupropion Centers for Disease Control and Prevention (U.S.)Cessation of life Chantix Chronic Cigarette Clinical Clinical Trials Control Groups Cues Data Developed Countries Development Dopamine Dose Dose-Limiting Economic Burden Epidemic Feeling Female Ganglia Genes Genetic Genetically Engineered Mouse Goals Health Health Care Costs Human In Vitro Individual Knock-out Knowledge Lead Learning Life Ligands Link Manic Mediating Mental disorders Methods Modeling Morbidity - disease rate Mus National Institute of Drug Abuse Nature Nausea Neurons Neurotransmitters Nicotine Nicotine Dependence Nicotine Withdrawal Nicotinic Receptors Norepinephrine Nose Participant Patients Pharmaceutical Preparations Pharmacology Physiological Placebo Control Placebos Plant Roots Point Mutation Productivity Prosencephalon Psychological reinforcement Public Health Rattus Recovery Reporting Research Schizophrenia Seeds Self Administration Self-Administered Signal Transduction Smoke Smoker Smoking Study Section Therapeutic Time Tobacco Tobacco use Toxic effect Up-Regulation Withdrawal Withdrawal Symptom World Health Organization addiction alpha-bungarotoxin receptor base cigarette smoking clinical efficacy cytisine desensitization design drug discrimination genetic manipulation health economics improved in vivo male mortality nicotine replacement nicotinic receptor alpha4beta2 novel pharmacokinetic characteristic pill premature prevent psychologic receptor receptor function smoking cessation success therapy design treatment duration uptake varenicline

项目摘要

DESCRIPTION (provided by applicant): The main hypothesis of the three projects included in this application is that many of the important in vivo effects of nicotine in the CNS are mediated mainly by the desensitization of neuronal nicotinic acetylcholine receptors (nAChRs), specifically a4p2 nAChRs, which are the major nAChR in the CNS and the one most clearly affected (up-regulated) by chronic administration of nicotine in rats and mice and by smoking in humans. Our hypothesis has deep roots in both cellular studies and studies ofthe in vivo effects of nicotine in animals going back more than 20 years. We recently reported that a new nAChR ligand sazetidine-A (Saz-A) is a selective a4|32 nAChR desensitizer. Thus its major in vitro effect is to desensitize 04(32 nAChRs without affecting either a3p4 or a7 nAChRs. Of particular importance, Saz-A in vivo can substitute for nicotine in drug discrimination studies and, even more important, it decreases nicotine self-administration in rats. We therefore propose further in depth studies of the effects of Saz-A, including its effects during chronic administration, as well as the synthesis and development of additional new selective a4p2 desensitizing ligands. Our proposed research consists of three projects. In Project 1, we will use pharmacological methods to characterize new ligands at nAChRs in vitro, as we have done for Saz-A. These in vitro cellular studies will identify the best candidates for detailed in vivo studies outlined in Project 2. In Project 2, the effects of Saz-A and additional ligands identified in project 1 will be further evaluated for their effects on nicotine self-administration in the rat model. In Project 3, synthesis of new ligands based on Saz-A will be carried out to optimize the new ligands, with respect to their pharmacology and pharmacokinetic characteristics, which will allow selection of the dose range for the in vivo studies of project 2. In addition, project 3 will provide acute toxicity data for promising ligands and will synthesize the ligands in the quantities necessary for the detailed in vivo studies in project 2. A major goal of our proposed research is that it will lead to the development a new class of CNS therapeutics, selective a4p2 nAChR desensitizers, to aid smoking cessation.

描述（申请人提供）：本申请中包括的三个项目的主要假设是，尼古丁在CNS中的许多重要体内作用主要由神经元烟碱乙酰胆碱受体（nAChR），特别是α 4 β 2 nAChR的脱敏介导，其是CNS中的主要nAChR，并且是在大鼠和小鼠中受尼古丁慢性给药以及在人类中受吸烟影响最明显（上调）的一种。我们的假设有着20多年的细胞研究和尼古丁在动物体内作用的研究基础。我们最近报道了一个新的nAChR配体sazetidine-A（Saz-A）是一个选择性的a4| 32 nAChR脱敏剂。因此，其主要的体外作用是使α 4 β 2 nAChR脱敏而不影响α 3 β 4或α 7 nAChR。特别重要的是，Saz-A在体内可以在药物辨别研究中替代尼古丁，更重要的是，它减少了大鼠的尼古丁自我给药。因此，我们建议进一步深入研究Saz-A的作用，包括其在慢性给药期间的作用，以及合成和开发额外的新的选择性α 4 β 2脱敏配体。我们提出的研究包括三个项目。在项目1中，我们将使用药理学方法在体外表征nAChRs的新配体，就像我们对Saz-A所做的那样。这些体外细胞研究将确定项目2中概述的详细体内研究的最佳候选者。在项目2中，将进一步评价项目1中确定的Saz-A和其他配体对大鼠模型中尼古丁自我给药的影响。在项目3中，将进行基于Saz-A的新配体的合成，以优化新配体的药理学和药代动力学特征，这将允许选择项目2体内研究的剂量范围。此外，项目3将提供有希望的配体的急性毒性数据，并将合成项目2详细体内研究所需数量的配体。我们提出的研究的一个主要目标是，它将导致开发一类新的CNS治疗剂，选择性a4 p2 nAChR脱敏剂，以帮助戒烟。

项目成果

期刊论文数量（10）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Preclinical studies of the potent and selective nicotinic α4β2 receptor ligand VMY-2-95.

DOI：
10.1021/mp5003569
发表时间：
2015-02-02
期刊：
Molecular pharmaceutics
影响因子：
4.9
作者：
Kong H;Song JK;Yenugonda VM;Zhang L;Shuo T;Cheema AK;Kong Y;Du GH;Brown ML
通讯作者：
Brown ML

Effects of chronic sazetidine-A, a selective α4β2 neuronal nicotinic acetylcholine receptors desensitizing agent on pharmacologically-induced impaired attention in rats.

慢性sazetidine-A，一种选择性α4β2 神经元烟碱乙酰胆碱受体脱敏剂对药理学诱导的大鼠注意力受损的影响。

DOI：
10.1007/s00213-012-2895-6
发表时间：
2013
期刊：
Psychopharmacology
影响因子：
3.4
作者：
Rezvani,AmirH;Cauley,Marty;Xiao,Yingxian;Kellar,KennethJ;Levin,EdwardD
通讯作者：
Levin,EdwardD

Absolute Configuration and Pharmacology of the Poison Frog Alkaloid Phantasmidine.

DOI：
10.1021/acs.jnatprod.8b00062
发表时间：
2018-04-27
期刊：
Journal of natural products
影响因子：
5.1
作者：
Fitch RW;Snider BB;Zhou Q;Foxman BM;Pandya AA;Yakel JL;Olson TT;Al-Muhtasib N;Xiao Y;Welch KD;Panter KE
通讯作者：
Panter KE