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.

项目摘要/摘要 人类成像，死后分析和动物模型的证据表明，神经元的萎缩 前额叶皮层（PFC）在神经精神病和神经生理学中起关键作用 神经退行性疾病。结构变化 - 包括树突轴的缩回，树突状的丧失 刺和突触密度的降低 - 实现功能性的定义是认知受损的， 减少动机，紧张局势，高焦虑和增加的冲动性。那是治疗策略的目的 恢复PFC结构/功能具有广泛的治疗潜力。精神质量量 - 小分子 促进PFC中的结构和功能性神经可塑性 - 生产快速和持久的疗法 一次给药后的效果。但是，许多精神质量量，包括氯胺酮和血清素能 迷幻药，引起幻觉，极大地限制了其治疗潜力和临床可伸缩性。 幸运的是，越来越多的证据表明氯胺酮和迷幻药的致幻作用可能 对于它们的治疗特性不是必需的，我们的小组最近引入了第一个非凝糖剂 精神质量量。非凝糖剂精神质质量的冒险代表了一个令人兴奋的新方向 为了治疗许多脑部疾病，但迫切需要进一步优化其效率和 安全概况。我们的主要目标是，1）建立强大的综合策略以自然 产品和化学脚手架可适应医学化学，2）发展高通量细胞 评估精神病效率和安全性的测定，以及3）预先适合新的体内测定 评估精神质质体的持久作用。综上所述，这些努力将使结构 - 活动关系（SAR）研究关键的精神碎裂脚手架的研究，填补了我们有关的空白 哪些结构基序对于精神构成和致幻作用至关重要。最终，工作 此处描述的将使迷幻的更安全，非避难剂替代品的合理设计 治疗多种神经精神病学和神经退行性疾病。