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Novel modulation of serotonin receptors

血清素受体的新调节

基本信息

批准号：
8049721
负责人：
Milton Teitler
金额：
$ 33.24万
依托单位：
ALBANY MEDICAL COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-07-01 至 2014-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8049721
关键词：
Affinity Aftercare Agonist Allosteric Regulation Allosteric Site Antipsychotic Agents Arrestins Binding Binding Sites Brain Cell Line Cell physiology Cells Clozapine Confocal Microscopy Coupled Cyclic AMP Data Dependence Development Disease Drug Receptors Excision Exposure to Functional disorder Funding G Protein-Coupled Receptor Genes GTP-Binding Proteins Grant Incubated Laboratories Lead Link MAP Kinase Gene Mental Depression Methiothepin Molecular Conformation Monitor Pharmaceutical Preparations Phosphorylation Procedures Production Property Protein Isoforms Psyche structure Psychopathology Radiolabeled Receptor Cell Receptor Mediated Signal Transduction Relative (related person)Research Design Research Proposals Risperidone Schizophrenia Series Serotonin Site System Therapeutic Time Western Blotting Work atypical antipsychotic beta-arrestin cell preparation improved mesulergine novel novel therapeutics prevent radioligand radiotracer receptor receptor binding receptor internalization research study response serotonin 7 receptor serotonin receptor stable cell line

项目摘要

DESCRIPTION (provided by applicant): Novel mechanisms of modulating GPCR function may result in improved therapeutics for treating many diseases including schizophrenia and depression. Studies performed during the previous funding cycle of this grant revealed two unexpected effects of drugs on h5-HT6 and h5-HT7 receptor activity. 1. Two groups of inverse agonists have been discovered: "high affinity/high potency" inverse agonists with potencies that are predicted from their affinities for the receptor, and "high affinity/low potency" inverse agonists with potencies that are far lower than predicted from their binding affinities for the receptor. 2.The second unexpected result is that risperidone (a widely prescribed antipsychotic drug), 9-OH-risperidone (the active metabolite of risperidone), and methiothepin produce a rapid and potent inactivation of the native h5-HT7 receptor (inactivating antagonists). Therefore, this proposal involves two specific aims: 1) determine the mechanism of action of high potency vs. low potency inverse agonists at CAM h5-HT6 and 5-HT7 receptors; and 2) determine the mechanism(s) of action that results in risperidone's rapid and potent inactivation of the native h5-HT7 receptor. Specific aim"1 will be approached in three ways: a) detailed pharmacological analysis of the actions of inverse agonists at the CAM h5-HT6 and h5-HT7 receptors to determine if an allosteric mechanism may be involved; b) monitor the effects of inverse agonists on CAM h5-HT6 and h5- HT7 receptor internalization and beta-arrestin translocation; c) monitor the effects of inverse agonists on CAM h5-HT6 and h5-HT7 receptor associated MARK activity. Specific aim 2 will be approached in three ways: a) determine if inactivating antagonists interact irreversibly with the native h-5HT7 receptor in intact cell preparations; b) monitor the effects of inactivating antagonists on native h5-HT7 receptor internalization and beta-arrestin translocation, and c) monitor the effects of inactivating antagonist treatment on MARK activity in cells expressing native h5-HT7 receptors. The results from these studies may reveal novel mechanisms for modulating the functional state of h5-HT6 and h5-HT7 receptors, which may be applicable to many other GPCR. Dysfunctions of these modulating mechanisms may underly the psychopathology of various mental diseases. These studies may lead to the development of novel therapeutics for brain dysfunctions, including schizophrenia and depression.

描述（由申请人提供）：调节 GPCR 功能的新机制可能会改善治疗许多疾病（包括精神分裂症和抑郁症）的疗法。在本次资助的上一个资助周期中进行的研究揭示了药物对 h5-HT6 和 h5-HT7 受体活性的两种意想不到的影响。 1. 已发现两组反向激动剂：“高亲和力/高效力”反向激动剂，其效力根据其与受体的亲和力预测；以及“高亲和力/低效力”反向激动剂，其效力远低于其与受体的结合亲和力预测的效力。 2.第二个意想不到的结果是利培酮（一种广泛使用的抗精神病药）、9-OH-利培酮（利培酮的活性代谢物）和甲硫替平可快速有效地灭活天然 h5-HT7 受体（灭活拮抗剂）。因此，该提案涉及两个具体目标：1）确定高效与低效反向激动剂对 CAM h5-HT6 和 5-HT7 受体的作用机制； 2) 确定导致利培酮快速有效灭活天然 h5-HT7 受体的作用机制。具体目标1将通过三种方式实现：a) 详细药理学分析反向激动剂对 CAM h5-HT6 和 h5-HT7 受体的作用，以确定是否可能涉及变构机制；b) 监测反向激动剂对 CAM h5-HT6 和 h5-HT7 受体内化和 β-抑制蛋白易位的影响；c) 监测反向激动剂对 CAM h5-HT6 和 h5-HT7 受体的影响。 h5-HT7 受体相关的 MARK 活性。具体目标 2 将通过三种方式实现：a) 确定失活拮抗剂是否与完整细胞制剂中的天然 h-5HT7 受体不可逆地相互作用； b) 监测失活拮抗剂对天然 h5-HT7 受体内化和 β-arrestin 易位的影响，以及 c) 监测失活拮抗剂治疗对表达天然 h5-HT7 的细胞中 MARK 活性的影响受体。这些研究的结果可能揭示调节 h5-HT6 和 h5-HT7 受体功能状态的新机制，这可能适用于许多其他 GPCR。这些调节机制的功能障碍可能是各种精神疾病的精神病理学的基础。这些研究可能会导致开发出治疗脑功能障碍（包括精神分裂症和抑郁症）的新疗法。