NEW METHODOLOGIES FOR THE SYNTHESIS OF NICOTINIC RECEPTOR AGONISTS

烟碱受体激动剂合成的新方法

• 批准号: 8360150
• 负责人: MARGARITA ORTIZ
• 金额: $ 10.35万
• 依托单位: UNIVERSITY OF PUERTO RICO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8360150
• 关键词: Address; Affect; Affinity; Agonist; Alzheimer' s Disease; Amino Alcohols; Antioxidants; Area; Attention; Biological; Biological Testing; Biology; Biomedical Research; Boranes; Chemicals; Cholinesterase Inhibitors; Complex; Computing Methodologies; Correlation Studies; Degenerative Disorder; Development; Esters; Ethers; Funding; Gilles de la Tourette syndrome; Goals; Grant; Hyperactive behavior; Imines; Ketones; Laboratories; Mediating; Methodology; Methods; Modeling; Molecular Models; Mus; National Center for Research Resources; Neurobiology; Neurodegenerative Disorders; Neuromuscular Junction; Neurons; Nicotine; Nicotinic Receptors; Oocytes; Oximes; Parkinson Disease; Pharmaceutical Preparations; Preparation; Principal Investigator; Property; Protocols documentation; Puerto Rico; Reaction; Reagent; Recombinants; Research; Research Infrastructure; Resources; Schizophrenia; Source; Structure; Testing; United States National Institutes of Health; Voltage-Clamp Technics; Work; analog; catalyst; cost; design; molecular modeling; novel; receptor; stereochemistry

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. The main goal of this project is to continue developing novel organic synthetic methodology for the preparation of potential nicotinic receptor agonist that will be valuable for the treatment of neuron-degenerative diseases, such Alzheimer and Parkinson, schizophrenia, attention deficit/hyperactivity and Tourette's syndrome and in the treatment of nicotine addition. In general, our work will focus on four major research areas: 1) development of new methodology for the asymmetric synthesis of biological important pyridyl and heterocyclic amino derivatives using our recently developed spiroborate catalysts for the reduction of ketones and oxime ethers; 2) design and synthesized novel chiral nicotinic analogs and of chiral drugs for neurodegenerative diseases; 3) biological testing of the new synthesized compounds as nicotinic receptor agonist, acetyl cholinesterase inhibitors and possibly, with antioxidant properties carried out in Dr. Lasalde Neurobiology Laboratory at UPR, Biology Department; and 4) study the structural factors affecting the reactivity and stereochemistry of the catalysts in the proposed synthetic methodology, in addition to the structure-activity studies that will be addressed by the CoPI, Dr. Carmelo Garcia, from UPR-Humacao using Gaussian 03 or Spartan 2.0 chemical computational methods. The results on this proposed interdisciplinary project on the search for new method for potential new nAChRs agonist are expected to strengthen our research capability for the submission of an RO1 proposal. Specific Aims: 1) To investigate the borane-mediated reduction of prochiral multifunctional ketones and oximes using spiroborate reagents and study their transformation to more complex chiral amino ethers, amino alcohols and diamino compounds. 2) To explored the use of spiroborate ester catalyst for the asymmetric reduction of model A/-substitute imines. 3) To establish protocols for the synthesis of novel alcohols and amino derivatives as nicotinic receptor agonist with multifunctional neuronal functions. 4) To test the new amino compounds as potential agonists for neuronal nicotinic receptors (nAChRs) and cholinesterase inhibitors using voltage clamp techniques and recombinant expression of nAChRs in oocytes and its electrophysiological characterization at mice neuromuscular junction. 5) To establish the optimal stereochemistry of chiral reagents and transition states for the proposed enantioselective reactions using molecular modeling methods. Molecular modeling will also be used to study the correlation between agonist's structure and observed and calculated affinities for the nACH receptors.

这个子项目是利用资源的许多研究子项目之一。 由NIH/NCRR资助的中心拨款提供。对子项目的主要支持 子项目的首席调查员可能是由其他来源提供的， 包括美国国立卫生研究院的其他来源。为子项目列出的总成本可能 表示该子项目使用的中心基础设施的估计数量， 不是由NCRR赠款提供给次级项目或次级项目工作人员的直接资金。 该项目的主要目标是继续开发新的有机合成方法，以制备潜在的尼古丁受体激动剂，这些方法将对治疗神经元退行性疾病，如阿尔茨海默氏症和帕金森病、精神分裂症、注意力缺陷/多动症和抽动症以及尼古丁增加的治疗有价值。总体而言，我们的工作将集中在四个主要研究领域：1)发展新的不对称方法 使用我们最新开发的螺硼酸酯催化剂用于酮和肟醚的还原，合成了生物上重要的吡啶和杂环氨基衍生物；2)设计和合成了新型手性烟碱类似物和 治疗神经退行性疾病的手性药物；3)新合成化合物作为烟碱受体激动剂、乙酰胆碱酯酶抑制剂以及可能具有抗氧化性能的生物测试，由Lasalde博士进行 4)在拟议的合成方法中研究影响催化剂反应性和立体化学的结构因素，此外，来自UPR-Humacao的Copi Carmelo Garcia博士将使用Gauss03或Spartan 2.0化学计算方法进行结构-活性研究。这项关于寻找潜在新的nAChRs激动剂的新方法的跨学科项目的结果有望加强我们提交RO1提案的研究能力。 具体目标： 1)考察了螺硼酸酯试剂对前手性多官能团酮类化合物的催化还原作用，并研究了它们转化为更复杂的手性氨基醚、氨基醇和二氨基化合物的反应。 2)探索螺硼酸酯催化剂在模型A/-取代亚胺不对称还原反应中的应用。 3)建立具有多功能神经功能的新型烟碱受体激动剂醇类和氨基类化合物的合成方案。 4)用电压钳技术检测新的氨基酸化合物作为神经元烟碱受体(NAChRs)和胆碱酯酶抑制剂的潜在激动剂，并在卵母细胞中重组表达nAChRs及其在小鼠神经肌肉接头处的电生理特性。 5)用分子模拟方法确定手性试剂和过渡态的最佳立体化学。分子模型也将被用来研究激动剂的结构与观察到的和计算出的NACH受体亲和力之间的相关性。