NICOTINIC CHOLINERGIC RECEPTOR AGONISTS

烟碱胆碱能受体激动剂

• 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
• 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

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α 7烟碱受体激动剂，已被广泛测试， 临床前和Phasel和精神分裂症的2项临床试验。这种化合物是一种弱的部分激动剂 血浆半衰期相对较短。它已被证明可以增强各种认知措施，包括 注意力和感觉门控的增加。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， 合成DMXB-A显示出与商品相当的化学纯度， 生产规范（GMP）标准。这将需要合成人的大部分要求的努力， 化学家为该项目的第一年。该核心的第二个功能是测量来自以下人群的血浆样本： 动物和人类已被给予DMXB-A，以确定其浓度和其 活性代谢物这将根据先前报告的HPLC方案进行，该方案允许同时 母体化合物及其4-OH、2-OH和2，4-二羟基代谢物的测量。这些代谢物 是有效的完全激动剂，并可能参与对DMXB-A给药的神经生物学反应。 这些数据将允许测试临床效果和血浆药物水平之间的相关性。的最终功能 核心将是鉴定和合成提供额外的相关化合物用于临床试验。 核心C为项目1提供临床研究支持，为项目4、5和6提供基础研究支持。 相关性（参见说明）： 精神分裂症需要新的治疗策略来改善认知功能障碍和负性 症状并预防精神病的发展。该中心研究了一种烟碱乙酰胆碱 受体作为新的治疗靶点。研究结果用于设计一种新的药物治疗， 精神分裂症和婴儿发育期间的预防性营养干预，这两者都激活了这一点。 r（=^r.e^rifnr