Chemical and Molecular Tools for Modulating GPCR Function

项目总结/摘要 来自人类成像、死后分析和动物模型的证据表明， 前额叶皮层（PFC）在神经精神和神经精神疾病的病理生理学中起着关键作用。 神经退行性疾病结构变化-包括树枝状乔木的收缩，树枝状的损失， 脊椎，和突触密度的减少-导致功能缺陷，表现为认知受损， 动机下降，快感缺乏，高度焦虑，冲动增加。因此，治疗策略旨在 恢复PFC结构/功能具有广泛的治疗潜力。精神致塑体-小分子， 促进PFC的结构和功能神经可塑性-产生快速和持久的治疗 单次给药后的效果。然而，许多精神致质体，包括氯胺酮和多巴胺能， 致幻剂引起幻觉，这极大地限制了它们的治疗潜力和临床可扩展性。 幸运的是，越来越多的证据表明，氯胺酮和致幻剂的致幻作用可能 他们的治疗特性是不必要的，我们的团队最近推出了第一个非致幻药， 精神质体非致幻性精神致活素的出现代表了一个令人兴奋的新方向 用于治疗许多脑部疾病，但迫切需要进一步优化其疗效， 安全配置文件。我们的主要目标是，1）建立强大的合成策略，以心理塑成自然 产品和化学支架，适合药物化学，2）开发高通量细胞 用于评估精神可塑剂功效和安全性的测定，以及3）推进新的体内测定，其独特地适合于 来评估精神致活素的长期效果这些努力合在一起，将使结构- 活性关系（SAR）研究的关键psychoplastogenic支架，填补了差距，我们的知识， 哪些结构基序对致幻和致幻作用都至关重要。最终，工作 这里描述的将使合理的设计更安全，非致幻替代迷幻药， 治疗各种神经精神和神经退行性疾病。

PROJECT SUMMARY/ABSTRACT Evidence from human imaging, postmortem analysis, and animal models suggests that atrophy of neurons in the prefrontal cortex (PFC) plays a key role in the pathophysiology of both neuropsychiatric and neurodegenerative diseases. Structural changes—including retraction of dendritic arbors, loss of dendritic spines, and reductions in synapse density—lead to functional deficits that manifest as impaired cognition, decreased motivation, anhedonia, high anxiety, and increased impulsivity. Thus, therapeutic strategies aiming to restore PFC structure/function have broad therapeutic potential. Psychoplastogens—small molecules that promote structural and functional neuroplasticity in the PFC—produce both rapid and long-lasting therapeutic effects after a single administration. However, many psychoplastogens, including ketamine and serotonergic psychedelics, induce hallucinations, which greatly limit their therapeutic potential and clinical scalability. Fortunately, increasing evidence suggests that the hallucinogenic effects of ketamine and psychedelics may not be necessary for their therapeutic properties, and our group recently introduced the first non-hallucinogenic psychoplastogens. The advent of non-hallucinogenic psychoplastogens represents an exciting new direction for the treatment of many brain disorders, but there is an urgent need to further optimize their efficacy and safety profiles. Our primary goals are to, 1) establish robust synthetic strategies to psychoplastogenic natural products and chemical scaffolds that are amenable to medicinal chemistry, 2) develop high-throughput cellular assays for assessing psychoplastogen efficacy and safety, and 3) advance new in vivo assays uniquely suited to evaluate the long-lasting effects of psychoplastogens. Taken together, these efforts will enable structure- activity relationship (SAR) studies of key psychoplastogenic scaffolds, filling the gap in our knowledge about which structural motifs are critical for both psychoplastogenic and hallucinogenic effects. Ultimately, the work described here will enable the rational design of safer, non-hallucinogenic alternatives to psychedelics for treating a wide variety of neuropsychiatric and neurodegenerative diseases.