Design, Synthesis, and Evaluation of Neural Plasticity-Promoting Analogs of Iboga and Ergoline Alkaloids

项目摘要/摘要 来自人体成像、尸检研究和动物模型的优势证据 提示前额叶皮质神经元萎缩在脑性痴呆的病理生理学中起关键作用。 神经精神疾病，如抑郁症、焦虑症和毒瘾。这些结构性的变化， 例如神经突起的收缩和树突棘的丧失，可能会被化合物所抵消 能够促进结构和功能神经的可塑性。事实上，神经可塑性的促进在 前额叶皮质已被认为在快速反应的治疗机制中起关键作用。 抗抑郁药和抗焦虑药，如氯胺酮。天然牛膝和麦角林家族中的化合物 产品在促进神经发生、脊髓形成和突触形成方面显示出巨大的潜力。 大脑皮层神经元，并表现出优于氯胺酮的促进可塑性的特性。然而，它是 目前尚不清楚这些分子的哪些结构特征有助于它们的疗效。我们的整体 目的是通过结构活性来生产更有效和更安全的促进可塑性的分子 这些关键脚手架的关系研究。为了获得所需的大量结构变体 对于这些研究，我们提出了新的合成路线，既可以合成伊波加，也可以合成麦角林类天然产物。 我们提出的策略比以前报道的合成要短得多，并且允许简便易行 多样化和模拟生成。我们设计和合成的化合物将使用 本实验室建立了一种新的体外神经可塑性分析方法。最终，这里描述的工作将填补这一空白 在我们关于分子结构如何影响神经可塑性的知识中，这将被证明有助于 下一代神经治疗学的发展。

PROJECT SUMMARY/ABSTRACT A preponderance of evidence from a combination of human imaging, postmortem studies, and animal models suggests that atrophy of neurons in the prefrontal cortex plays a key role in the pathophysiology of neuropsychiatric diseases such as depression, anxiety disorders, and addiction. These structural changes, such as the retraction of neurites and loss of dendritic spines, can potentially be counteracted by compounds capable of facilitating structural and functional neural plasticity. In fact, the promotion of neural plasticity in the prefrontal cortex has been proposed to play a crucial role in the therapeutic mechanism of fast-acting antidepressants and anxiolytics such as ketamine. Compounds from the iboga and ergoline families of natural products have shown enormous potential for promoting neuritogenesis, spinogenesis, and synaptogenesis in cortical neurons, and have demonstrated plasticity-promoting properties superior to ketamine. However, it is currently unknown which structural features of these molecules contribute to their efficacy. Our overall objective is to produce more effective and safer plasticity-promoting molecules through structure-activity relationship studies of these key scaffolds. To gain access to the large number of structural variants required for these studies, we propose novel synthetic routes to both the iboga and ergoline classes of natural products. The strategies we advance are significantly shorter than previously reported syntheses and allow for facile diversification and analog generation. The compounds that we design and synthesize will be assessed using novel in vitro neural plasticity assays developed in our lab. Ultimately, the work described here will fill the gap in our knowledge about how molecular structure impacts neural plasticity and will prove instrumental to the evolution of next-generation neurotherapeutics.