Design and Study of New Nicotinic Analogs for Use in Depression

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的尼古丁制剂。这一努力中的先导化合物属于AMOP-H-OH(6-[5-(azetidin-2-ylmethoxy)-pyridin-3-yl]-hex-5-yn-1-ol)系列产品。初步研究表明，其中一些药物对特定的烟碱型乙酰胆碱受体(NAChR)亚型具有很高的亲和力和选择性，通过行为研究评估，这些亚型与药物抗抑郁药信号非常相关。我们的工作假设是，作为部分激动剂且对由A4和-32亚基组成的nAChRs(a4p2-nAChRs)具有真正选择性的药物将具有预期的抗抑郁活性。该研究计划围绕三个相互交错的项目构建，并由一个行政核心提供支持。在药物化学项目1中，我们将通过改变在哺乳动物细胞或非洲爪哇卵母细胞中自然或异源表达的立体和立体电子人nAChR亚型来设计和合成新的AMOP-H-OH类似物。这项工作将确定新的配体是作为完全或部分激动剂，作为竞争性或非竞争性拮抗剂，作为开放或关闭的通道阻滞剂，还是作为功能nAChRs的正或负变构调节剂，如果可能的话，将基于现有的电生理记录技术和高通量同位素离子通量分析。在项目3中，还将使用创新、强大和高通量的SmartCube？1/2系统来确定新配体的行为特征，并通过更经典的方法进行增强，以评估作为抗抑郁剂的药物活动。这些研究将分一系列迭代进行，通过体外nAChR亚型药理分析、建模和体内行为测试，为合成策略提供信息，以优化化合物的nAChR亚型选择性和行为活性，使其逐渐优于与情绪和情绪有关的bestrs。然而，这项工作的主要重点是开发新的抗抑郁药物。相关性(参见说明书)：抗抑郁药物仍然存在重要的医学需求，表现出更快的起效，更少的副作用，以及以新的药理方式发挥作用。因此，我们选择集中精力开发我们的nAChR配体作为抗抑郁药物。然而，我们仍然对可能在其他一些临床应用中使用相同的化合物持开放态度，包括治疗尼古丁依赖、精神分裂症和疼痛。

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.