Design and Study of New Nicotinic Analogs for Use in Depression

用于治疗抑郁症的新型烟碱类似物的设计和研究

• 批准号: 7697562
• 负责人: alan P. kozikowski
• 金额: $ 96.42万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-10 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7697562
• 关键词: Design; Study; New; Nicotinic; Analogs

DESCRIPTION (provided by applicant): The goal of this NCDDDG research program is to identify new nicotinic agents that can be used in the treatment of depression. The lead compounds in this endeavor belong to the AMOP-H-OH (6-[5-(azetidin-2-ylmethoxy)-pyridin-3-yl]-hex-5-yn-1-ol) family of products. Preliminary studies show high affinities and selectivities of some of these agents for specific nicotinic acetylcholine receptor (nAChR) subtypes that correlate very well with drug antidepressant signatures as assessed by behavioral studies. Our working hypothesis is that drugs having high potency as partial agonists and that are truly selective for nAChRs composed of a4 and -32 subunits (a4p2-nAChRs) will have desired antidepressant activities. The research program is constructed around three, interlacing projects and supported by an administrative core. In the medicinal chemistry Project 1, we will design and synthesize new AMOP-H-OH analogs by varying their steric and stereoelectroman nAChR subtypes naturally or heterologously expressed in mammalian cells or Xenopus oocytes. This work will define whether new ligands act as full or partial agonists, as competitive or non-competitive antagonists, as open or closed channel blockers, or as positive or negative allosteric modulators at functional nAChRs based on established electrophysiological recording techniques and higher-throughput isotopic ion flux assays when possible. In Project 3, behavioral profiles for new ligands also will be determined using the innovative, powerful and high-throughput SmartCube?1/2 system, augmented by more classical methods, to assess drug activities as antidepressants. The studies will be conducted in a series of iterations, with in vitro nAChR subtype pharmacological profiling, modeling, and in vivo behavioral testing serving to inform synthetic strategies toward compounds that are optimized to have progressively superior nAChR subtype selectivity and behavioral activity The bestrs related to emotion and mood. However, the major focus of the work is to develop new antidepressant medications. RELEVANCE (See instructions): There still exists an important medical need for antidepressants exhibiting faster onsets of action, fewer side effects, and that act pharmacologically in new ways. Therefore, we have chosen to focus our efforts on the development of our nAChR ligands as antidepressants. However, we remain open to possible use of the same compounds in a number of other clinical applications, including treatment of nicotine dependence, schizophrenia, and pain.

描述（由申请人提供）：该NCDDDG研究计划的目标是确定可用于治疗抑郁症的新烟碱剂。这项努力中的铅化合物属于Amop-H-OH（6- [5-（azetidin-2-基甲氧基）-Pyridin-3-yl] -Hex-5-yn-1-Ol产品家族。初步研究表明，这些药物中的某些药物中的某些药物对特定的烟碱乙酰胆碱受体（NACHR）亚型的选择性高，这些亚型与行为研究评估的药物抗抑郁剂特征非常相关。我们的工作假设是，作为部分激动剂的药物具有很高的效力，并且对由A4和-32亚基（A4P2 -NACHRS）组成的NACHR确实具有选择性。该研究计划围绕三个交织项目构建，并由行政核心支持。在药物化学项目1中，我们将通过自然或在哺乳动物细胞或爪蟾卵母细胞中自然或异源表达其空间和立体传播的NACHR亚型来设计和合成新的Amop-H-OH类似物。这项工作将将新配体作为竞争性或非竞争性拮抗剂，开放或封闭的通道阻滞剂，还是基于既定的电生理记录技术的功能性NACHR，以及在可能的情况下，在功能性NACHRS上作为竞争性或封闭的变构调节器，将新配体作为竞争性或非竞争力拮抗剂，或者是正能量NACHR，以及在可能的情况下，将新配体作为竞争性或非竞争力的拮抗剂，或者将其作为竞争性或封闭的拮抗剂障碍物，以及在可能的较高关键的同位素离子液液（如果可能的情况下）在功能性NACHRS上作为正面或负面的变构调节剂。在项目3中，新配体的行为概况也将使用创新，功能强大且高通量的SmartCube？1/2系统（以更古典的方法增强）来评估药物活动作为抗抑郁药。这些研究将在一系列迭代中进行，并具有体外NACHR亚型药理分析，建模和体内行为测试，用于为合成策略提供了优化的合成策略，这些化合物已被优化，以逐步具有优质的NACHR亚型选择性和行为活动，与情绪和情绪相关。但是，这项工作的主要重点是开发新的抗抑郁药。相关性（请参阅说明）：仍然存在重要的医疗需求，抗抑郁药表现出更快的作用，副作用更少，并且以新的方式进行药理学。因此，我们选择将精力集中在纳入nachr配体作为抗抑郁药的发展上。但是，我们仍然可以在许多其他临床应用中可能使用相同的化合物，包括治疗尼古丁依赖性，精神分裂症和疼痛。