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

项目总结/摘要 来自人体成像、死后研究和动物模型的大量证据 表明前额叶皮层神经元的萎缩在脑卒中的病理生理学中起着关键作用。 神经精神疾病，如抑郁症、焦虑症和成瘾。这些结构性变化， 例如神经突的回缩和树突棘的丧失， 能够促进结构和功能的神经可塑性。事实上，促进神经可塑性在 前额叶皮层被认为在速效的治疗机制中起着至关重要的作用。 抗抑郁药和抗焦虑药，如氯胺酮。来自天然药物的伊波加和麦角灵家族的化合物 产品已经显示出巨大的潜力，促进神经突发生，棘发生，和突触发生， 皮质神经元，并已证明可塑性促进性能优于氯胺酮上级。但据 目前尚不清楚这些分子的哪些结构特征有助于它们的功效。我们的整体 目的是通过构效关系， 这些关键支架的关系研究。为了获得所需的大量结构变体， 对于这些研究，我们提出了iboga和ergoline类天然产物的新合成路线。 我们提出的策略比以前报道的合成要短得多， 多样化和模拟生成。我们设计和合成的化合物将通过使用 我们实验室开发的新型体外神经可塑性测定。最终，这里描述的工作将填补差距 在我们关于分子结构如何影响神经可塑性的知识中， 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.