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.

项目总结/文摘