Novel Triple Uptake Inhibitors for Treatment of Depression

用于治疗抑郁症的新型三重摄取抑制剂

基本信息

  • 批准号:
    8259537
  • 负责人:
  • 金额:
    $ 38.39万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2009
  • 资助国家:
    美国
  • 起止时间:
    2009-07-03 至 2014-04-30
  • 项目状态:
    已结题

项目摘要

Dutta, Aloke K Major depression disorder is a significant health problem and behind the cardiovascular disease, depression is considered as the second most debilitating disease in the world. Selective serotonin reuptake inhibitors (SSRIs) antidepressant agents have been limited by slow onset of action and also have been implicated recently in high adolescent suicide rate and other side effects. In spite of developments of different array of antidepressants, there still remains a significant unmet need for much more improved therapy, as large numbers of depressed people are still refractory to the current existing therapies. Ironically, in the current pharmacotherapy of depression, dopaminergic component has not been included when there are ample clinical and biochemical evidences pointing towards a strong dopaminergic component in depression. Recently, triple monoamine uptake inhibitors (TUI) interacting with dopamine, serotonin and norepinephrine transporters have been implicated in potent antidepressant activity. This is due to the fact that additional dopaminergic component can effectively relieve depression by activating mesocorticolimbic dopaminergic pathways in the reward system. This can act to reduce anhedonia, which is associated with a deficit in dopaminergic transmission and is a central component to a depressive state of mind. In our effort to discover and develop novel molecules for interaction with multiple monoamine transporters, we have recently developed asymmetric di- and tri- substituted pyran derivatives. Uptake inhibition studies with all three monoamine transporters indicated variety of activities depending upon the nature of substitutions either on the pyran ring or on the N-benzyl moiety. The preliminary results also indicated stereospecific requirement for interaction of these molecules with the monoamine transporters as the potent interaction was mostly exhibited in the (-)-isomers. Three different classes of molecules emerged from these studies and they are labeled as serotonin-norepinephrine reuptake inhibitors (SNRI), NRI and triple reuptake inhibitors (TUI). One of the lead TUI molecules, (-)-17a, exhibiting potent norepinephrine and serotonin inhibition (Ki; 5.09 and 37.7 nM, respectively) activity along with modest dopamine transporters uptake inhibition activity (Ki; 85 nM), was further evaluated in different in vivo depression animal model studies. In vivo results indicated (-)-17a could potently reduce immobility in rat forced swimm test and mice tail suspension test. Furthermore, locomotor activity results indicated that this reduction of immobility was not due to locomotor activation. We now plan to follow up on our preliminary SAR studies on these pyran derivatives to develop more suitable TUI lead molecules. Lead compounds with suitable properties will be evaluated for antidepressant properties in animal experiments. Two most potent antidepressant molecules will be tested for their antianxiety effect and also on expression of brain derived neurotrophic factor (BDNF), implicated in the clinical action of antidepressant drugs.
Dutta, Aloke K

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

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Aloke K Dutta其他文献

Aloke K Dutta的其他文献

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{{ truncateString('Aloke K Dutta', 18)}}的其他基金

Novel Triple Uptake Inhibitors for Treatment of Depression
用于治疗抑郁症的新型三重摄取抑制剂
  • 批准号:
    8066635
  • 财政年份:
    2009
  • 资助金额:
    $ 38.39万
  • 项目类别:
Novel Triple Uptake Inhibitors for Treatment of Depression
用于治疗抑郁症的新型三重摄取抑制剂
  • 批准号:
    7885638
  • 财政年份:
    2009
  • 资助金额:
    $ 38.39万
  • 项目类别:
Novel Triple Uptake Inhibitors for Treatment of Depression
用于治疗抑郁症的新型三重摄取抑制剂
  • 批准号:
    8463866
  • 财政年份:
    2009
  • 资助金额:
    $ 38.39万
  • 项目类别:
Novel Triple Uptake Inhibitors for Treatment of Depression
用于治疗抑郁症的新型三重摄取抑制剂
  • 批准号:
    7728202
  • 财政年份:
    2009
  • 资助金额:
    $ 38.39万
  • 项目类别:
Novel Neuroprotective Treatment for Parkinson's Disease
帕金森病的新型神经保护治疗
  • 批准号:
    7014046
  • 财政年份:
    2005
  • 资助金额:
    $ 38.39万
  • 项目类别:
Novel Neuroprotective Treatment for Parkinson's Disease
帕金森病的新型神经保护治疗
  • 批准号:
    8687751
  • 财政年份:
    2005
  • 资助金额:
    $ 38.39万
  • 项目类别:
Novel Neuroprotective Treatment for Parkinson's Disease
帕金森病的新型神经保护治疗
  • 批准号:
    8251673
  • 财政年份:
    2005
  • 资助金额:
    $ 38.39万
  • 项目类别:
Novel Neuroprotective Treatment for Parkinson's Disease
帕金森病的新型神经保护治疗
  • 批准号:
    6915939
  • 财政年份:
    2005
  • 资助金额:
    $ 38.39万
  • 项目类别:
Novel Neuroprotective Treatment for Parkinson's Disease
帕金森病的新型神经保护治疗
  • 批准号:
    7230944
  • 财政年份:
    2005
  • 资助金额:
    $ 38.39万
  • 项目类别:
Novel Neuroprotective Treatment for Parkinson's Disease
帕金森病的新型神经保护治疗
  • 批准号:
    8328605
  • 财政年份:
    2005
  • 资助金额:
    $ 38.39万
  • 项目类别:

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