Chemical and Molecular Tools for Modulating GPCR Function

用于调节 GPCR 功能的化学和分子工具

• 批准号: 10551701
• 负责人: David E Olson
• 金额: $ 37.56万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-06-01 至 2028-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10551701
• 关键词: Alzheimer' s Disease; Anhedonia; Animal Model; Anxiety; Atrophic; Autopsy; Biological Assay; Brain Diseases; Cellular Assay; Chemicals; Clinical; Dendritic Spines; Development; Disease; Engineering; Functional disorder; G-Protein-Coupled Receptors; Goals; Hallucinations; Hallucinogens; Impaired cognition; Impulsivity; Ketamine; Knowledge; Lead; Mental Depression; Methods; Molecular; Motivation; Natural Products; Neurodegenerative Disorders; Neuronal Plasticity; Neurons; Parkinson Disease; Pharmaceutical Chemistry; Play; Post-Traumatic Stress Disorders; Prefrontal Cortex; Property; Research; Safety; Structure; Structure-Activity Relationship; Substance Use Disorder; Synapses; Therapeutic; Therapeutic Effect; Traction; Work; analog; cerebral atrophy; density; human imaging; in vivo; neuropsychiatric disorder; rational design; scaffold; small molecule; tool

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.

项目概要/摘要 来自人类成像、尸检分析和动物模型的证据表明，神经元萎缩 前额皮质（PFC）在神经精神和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——包括树突乔木的缩回、树突的丧失 棘和突触密度的减少——导致功能缺陷，表现为认知受损， 动机降低、快感缺乏、高度焦虑和冲动增加。因此，治疗策略旨在 恢复 PFC 结构/功能具有广泛的治疗潜力。精神塑体素——小分子 促进前额皮质的结构和功能神经可塑性——产生快速和持久的治疗效果 单次给药后的效果。然而，许多精神塑性激素，包括氯胺酮和血清素能药物 致幻剂会引起幻觉，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 对于它们的治疗特性来说并不是必需的，我们的小组最近推出了第一个非致幻剂 精神塑性剂。非致幻性精神塑性剂的出现代表了一个令人兴奋的新方向 用于治疗多种脑部疾病，但迫切需要进一步优化其疗效和 安全概况。我们的主要目标是，1）建立强大的心塑性天然合成策略 适合药物化学的产品和化学支架，2）开发高通量细胞 评估精神质体原功效和安全性的测定，以及 3) 推进独特适合的新体内测定 评估精神塑性剂的长期影响。总而言之，这些努力将使结构 关键心理塑性支架的活性关系（SAR）研究，填补了我们在以下方面的知识空白： 哪些结构基序对于心塑性和致幻作用都至关重要。最终，工作 这里描述的将能够合理设计更安全、非致幻剂的迷幻药替代品 治疗多种神经精神疾病和神经退行性疾病。