NICOTINIC CHOLINERGIC RECEPTOR AGONISTS

烟碱胆碱能受体激动剂

基本信息

批准号：
8120343
负责人：
ROBERT R FREEDMAN
金额：
$ 11.89万
依托单位：
UNIVERSITY OF COLORADO DENVER
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：
2010-08-01 至 2014-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8120343
关键词：
ABT-418 AR-R 17779 Acetylcholine Affinity Agonist Amines Analytical Chemistry Animals Area Attention Auditory Basic Science Binding Biological Assay Biological Factors Blinded Brain Buffers Carboxylic Acids Characteristics Chemicals Choline Cholinergic Agents Cholinergic Agonists Cholinergic Receptors Chronic Clinical Clinical Research Clinical Trials Cognition Colorado Conflict of Interest DBA/2 Mouse Data Development Disease Dose Drug Compounding Drug Delivery Systems Drug Formulations Drug Kinetics Dryness Esters FDA approved Family suidae Figs - dietary Fingerprint Florida Funding GTS-21 Genetic Grant Half-Life High Pressure Liquid Chromatography Hippocampus (Brain)Hospitals Hour Human Hydroxyl Radical Impaired cognition In Vitro Individual Infant Development Inhibitory Concentration 50 Injection of therapeutic agent Instruction Intervention Investigation Joints Laboratories Legal patent Ligands Light Marine Toxins Measurement Measures Medical center Metabolism Methanol Methodology Methods Methylphenidate Molecular Weight Muscarinic Acetylcholine Receptor Neurobiology Nicotine Nicotinic Agonists Nicotinic Receptors Nitrogen Nutrient Nylons Oocytes Oral Administration Pamphlets Parents Patients Pattern Pepsin A Pharmaceutical Preparations Pharmacologic Substance Pharmacy facility Phase Phase I Clinical Trials Plasma Polymers Preparation Principal Investigator Property Protocols documentation Psychotic Disorders Publishing Pump Reaction Receptor Activation Recovery Regimen Relative (related person)Reporting Research Personnel Research Support Rights Rodent Role Sampling Schizophrenia Series Serotonin Receptors 5-HT-3 Smoking Sodium Chloride Solid Solutions Source Spectrum Analysis Structure Symptoms Testing Therapeutic Time Toxicology Universities Water Xenopus oocyte ammonium acetate anabaseine anabaseine dihydrochloride analog base behavior test capsule chemical property cholinergic clinical effect data sharing desensitization design detector deviant drug candidate expectation fluoromethyl 2,2-difluoro-1-(trifluoromethyl)vinyl ether human subject human subject protection improved infrared spectroscopy interest new therapeutic target nonane novel therapeutics phase 1 study pre-clinical preclinical safety prevent programs receptor research clinical testing research study response sensory gating silochrome stability testing

项目摘要

DMXB-A is a prototypic selective alpha7 nicotinic receptor agonist that has been tested extensively both preclinically and in Phasel and 2 clinical tests in schizophrenia. This compound is a weak partial agonist with relatively short plasma half-life. It has been shown to enhance various measures of cognition including increases in attention and sensory gating. The purpose of this Core project is to synthesize DMXB-A in sufficient amounts and purity for further clinical and pre-clinical tests. The FDA has stipulated that the synthetic DMXB-A display a chemical purity equivalent to a commercial product made under Good Manufacturing Practice (GMP) standards. This will require most of the requested effort of the synthetic chemist for Year 1 of the project. A second function of this Core will be to measure plasma samples from animals and humans that have been administered DMXB-A to determine its concentration and those of its active metabolites. This will be done according to previously reported HPLC protocols that allow concurrent measurement of parent compound and its 4-OH, 2-OH, and 2,4-Dihydroxy metabolites. These metabolites are potent full agonists and may be involved in the neurobiological response to DMXB-A administration. These data will allow tests of correlation between clinical effect and plasma drug levels. The final function of the Core will be to identify and synthetically provide additional related compounds for clinical tests. Core C provides clinical research support to Project 1 and basic research support to Projects 4, 5, and 6. RELEVANCE (See instructions): New therapeutic strategies for schizophrenia are needed to improve cognitive dysfunction and negative symptoms and to prevent the development of psychosis. The Center investigates a nicotinic acetylcholine receptor as a new therapeutic target. Investigational results are used to design a new drug treatment for schizophrenia and a preventative nutrient intervention during infant development, both of which activate this r(=^r.e^rifnr

DMXB-A是一种原型选择性α7烟碱受体激动剂，已被广泛测试精神分裂症中的临床上和阶段和2个临床测试。该化合物是弱的部分激动剂血浆半衰期相对较短。已证明它可以增强认知的各种措施注意力和感官门控的增加。该核心项目的目的是合成DMXB-A 足够的量和纯度，用于进一步的临床和临床前测试。 FDA规定了合成DMXB-A显示出与良好生产的商业产品等效的化学纯度制造实践（GMP）标准。这将需要合成的大部分要求的努力该项目第一年的化学家。该核心的第二个功能将是测量来自已施用DMXB-A的动物和人类确定其浓度及其浓度活性代谢物。这将根据先前报道的HPLC协议来完成，该协议允许并发父母化合物及其4-OH，2-OH和2,4-二羟基代谢物的测量。这些代谢物是有效的全部激动剂，可能参与对DMXB-A给药的神经生物学反应。这些数据将允许测试临床效应和血浆药物水平之间的相关性。的最终功能核心将是识别并合成为临床测试提供其他相关化合物。 Core C为项目1，项目4、5和6提供了临床研究支持，并为基础研究提供了支持。相关性（请参阅说明）：需要针对精神分裂症的新治疗策略来改善认知功能障碍和阴性症状并防止精神病的发展。该中心研究了烟碱乙酰胆碱受体作为新的治疗靶点。研究结果用于设计一种新药物治疗精神分裂症和婴儿发育过程中的预防养分干预措施，这两者都激活了这一点 r（=^r.e^rifnr