Design and Study of New Nicotinic Analogs for Use in Depression

描述（由申请人提供）：本NCDDDG研究计划的目标是确定可用于治疗抑郁症的新烟碱类药物。在这一奋进中的先导化合物属于AMOP-H-OH（6-[5-（氮杂环丁烷-2-基甲氧基）-吡啶-3-基]-己-5-炔-1-醇）产品家族。初步研究显示，这些药物中的一些对特定烟碱乙酰胆碱受体（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剂特征非常相关。我们的工作假设是，作为部分激动剂具有高效力并且对由α 4和α 32亚基组成的nAChR（α 4 β 2-nAChR）具有真正选择性的药物将具有期望的抗抑郁活性。该研究计划围绕三个相互交织的项目构建，并得到行政核心的支持。在药物化学项目1中，我们将设计和合成新的AMOP-H-OH类似物，通过改变它们在哺乳动物细胞或非洲爪蟾卵母细胞中天然或异源表达的空间和立体电生理nAChR亚型。这项工作将确定新的配体是否作为完全或部分激动剂，作为竞争性或非竞争性拮抗剂，作为开放或封闭通道阻滞剂，或作为积极或消极的变构调节剂在功能nAChRs的基础上建立电生理记录技术和更高的通量同位素离子通量测定时，可能的。在项目3中，新配体的行为特征也将使用创新的，强大的和高通量的SmartCube？1/2系统，通过更经典的方法增强，以评估药物作为抗抑郁药的活性。这些研究将以一系列迭代进行，体外nAChR亚型药理学分析、建模和体内行为测试用于为优化化合物的合成策略提供信息，这些化合物具有渐进的上级nAChR亚型选择性和行为活性。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.