Design and Study of New Nicotinic Analogs for Use in Depression

描述（由申请人提供）：本NCDDDG研究项目的目标是确定可用于治疗抑郁症的新型尼古丁制剂。这项研究的先导化合物属于AMOP-H-OH（6-[5-（叠氮丁-2-基甲氧基）-吡啶-3-基]-己-5-炔-1-醇）家族产物。初步研究表明，其中一些药物对特定的尼古丁乙酰胆碱受体（nAChR）亚型具有高亲和力和选择性，这些亚型与行为研究评估的药物抗抑郁特征非常相关。我们的工作假设是，作为部分激动剂的高效药物，对a4和-32亚基组成的nAChRs （a4p2-nAChRs）具有真正的选择性，将具有理想的抗抑郁活性。该研究项目围绕三个相互交错的项目构建，并由行政核心提供支持。在药物化学项目1中，我们将通过改变AMOP-H-OH在哺乳动物细胞或非洲爪蟾卵母细胞中自然或异源表达的立体和立体电子nAChR亚型，设计和合成新的AMOP-H-OH类似物。这项工作将根据已建立的电生理记录技术和高通量同位素离子通量测定，确定新配体在功能性nachr中是作为完全或部分激动剂、竞争或非竞争拮抗剂、开放或封闭通道阻滞剂，还是作为正或负变构调节剂。在项目3中，新配体的行为特征也将使用创新的、强大的、高通量的SmartCube？1/2系统，通过更经典的方法增强，来评估药物作为抗抑郁药的活性。这些研究将在一系列的迭代中进行，包括体外nAChR亚型药理学分析、建模和体内行为测试，以提供合成策略，以优化具有逐渐优越的nAChR亚型选择性和行为活性的化合物，这些化合物与情绪和情绪有关。然而，这项工作的主要重点是开发新的抗抑郁药物。

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.