Novel modulation of serotonin receptors

血清素受体的新调节

基本信息

  • 批准号:
    7800246
  • 负责人:
  • 金额:
    $ 37.81万
  • 依托单位:
  • 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 2012-03-31
  • 项目状态:
    已结题

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功能的新机制可能导致用于治疗包括精神分裂症和抑郁症在内的许多疾病的改进的治疗剂。在该资助的上一个资助周期进行的研究揭示了药物对h5-HT 6和h5-HT 7受体活性的两种意想不到的影响。1.已经发现了两组反向激动剂:“高亲和力/高效力”反向激动剂,其效力由其对受体的亲和力预测,和“高亲和力/低效力”反向激动剂,其效力远低于由其对受体的结合亲和力预测。2.第二个意想不到的结果是利培酮(一种广泛处方的抗精神病药物)、9-OH-利培酮(利培酮的活性代谢物)和甲硫替平产生天然h5-HT 7受体的快速和有效的失活(失活拮抗剂)。因此,该提议涉及两个具体目的:1)确定高效与低效反向激动剂对CAM h5-HT 6和5-HT 7受体的作用机制;和2)确定导致利培酮快速和有效灭活天然h5-HT 7受体的作用机制。具体目标“1将以三种方式实现:a)对CAM h5-HT 6和h5-HT 7受体的反向激动剂的作用进行详细的药理学分析,以确定是否可能涉及变构机制; B)监测反向激动剂对CAM h5-HT 6和h5-HT 7受体内化和β-抑制蛋白易位的作用; c)监测反向激动剂对CAM h5-HT 6和h5-HT 7受体相关MARK活性的影响。具体目标2将以三种方式实现:a)确定灭活拮抗剂是否与完整细胞制备物中的天然h-5 HT 7受体不可逆地相互作用; B)监测灭活拮抗剂对天然h-5 HT 7受体内化和β-抑制蛋白易位的影响,和c)监测灭活拮抗剂处理对表达天然h-5 HT 7受体的细胞中MARK活性的影响。这些研究的结果可能揭示了调节h5-HT 6和h5-HT 7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基础。这些研究可能会导致开发新的治疗脑功能障碍的药物,包括精神分裂症和抑郁症。

项目成果

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Milton Teitler其他文献

Milton Teitler的其他文献

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{{ truncateString('Milton Teitler', 18)}}的其他基金

Human 5HT 1E Serotonin Receptor Drug Development (RMI)
人类 5HT 1E 血清素受体药物开发 (RMI)
  • 批准号:
    7057555
  • 财政年份:
    2005
  • 资助金额:
    $ 37.81万
  • 项目类别:
Molecular Biology of 5HT2A receptor expressing synapses
5HT2A 受体表达突触的分子生物学
  • 批准号:
    6782269
  • 财政年份:
    2004
  • 资助金额:
    $ 37.81万
  • 项目类别:
Molecular Biology of 5HT2A receptor expressing synapses
5HT2A 受体表达突触的分子生物学
  • 批准号:
    6869606
  • 财政年份:
    2004
  • 资助金额:
    $ 37.81万
  • 项目类别:
CONSTITUTIVELY ACTIVE SEROTONIIN RECEPTORS
组成型活性血清素受体
  • 批准号:
    2675594
  • 财政年份:
    1997
  • 资助金额:
    $ 37.81万
  • 项目类别:
CONSTITUTIVELY ACTIVE SEROTONIN RECEPTORS
组成型活性血清素受体
  • 批准号:
    6334343
  • 财政年份:
    1997
  • 资助金额:
    $ 37.81万
  • 项目类别:
Novel modulation of serotonin receptors
血清素受体的新调节
  • 批准号:
    7675179
  • 财政年份:
    1997
  • 资助金额:
    $ 37.81万
  • 项目类别:
CONSTITUTIVELY ACTIVE SEROTONIIN RECEPTORS
组成型活性血清素受体
  • 批准号:
    2404688
  • 财政年份:
    1997
  • 资助金额:
    $ 37.81万
  • 项目类别:
CONSTITUTIVELY ACTIVE SEROTONIN RECEPTORS
组成型活性血清素受体
  • 批准号:
    6878503
  • 财政年份:
    1997
  • 资助金额:
    $ 37.81万
  • 项目类别:
Novel modulation of serotonin receptors
血清素受体的新调节
  • 批准号:
    8049721
  • 财政年份:
    1997
  • 资助金额:
    $ 37.81万
  • 项目类别:
CONSTITUTIVELY ACTIVE SEROTONIN RECEPTORS
组成型活性血清素受体
  • 批准号:
    6724895
  • 财政年份:
    1997
  • 资助金额:
    $ 37.81万
  • 项目类别:

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