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：
Aloke K Dutta
金额：
$ 38.39万
依托单位：
WAYNE STATE UNIVERSITY
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

来源：
https://reporter.nih.gov/project-details/8259537
关键词：
Acute Address Adolescent Adverse effects Affinity Aftercare Anhedonia Animal Experiments Animal Model Anti-Anxiety Agents Antidepressive Agents Biochemical Biological Availability Brain-Derived Neurotrophic Factor Cardiovascular Diseases Cell Line Chronic Clinic Clinical Data Depressed mood Development Disease Disease remission Dopamine Dose Drug Kinetics Enrollment Exhibits Goals Health Hippocampus (Brain)Human Cloning In Vitro Individual Isomerism Label Lead Life Locomotion Major Depressive Disorder Measures Mental Depression Methods Mind Modeling Modification Molecular Motor Activity Mus Nature Norepinephrine Pathway interactions Patients Pharmacotherapy Production Property Pyrans Rattus Refractory Relapse Rewards Role Selective Serotonin Reuptake Inhibitor Serotonin Structure-Activity Relationship Swimming System Tail Suspension Testing Unipolar Depression base depressive symptoms design dopamine transporter fluoromethyl 2,2-difluoro-1-(trifluoromethyl)vinyl ether follow-up frontal lobe functional group improved in vitro testing in vivo inhibitor/antagonist monoamine noradrenaline transporter norepinephrine system novel pharmacophore piperidine research study response reuptake serotonin transporter suicidal act suicide rate tool transmission process uptake

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.

阿洛克·K·杜塔重度抑郁症是一个严重的健康问题，在心血管疾病的背后，抑郁症是被认为是世界上第二大使人衰弱的疾病。选择性血清素再摄取抑制剂（SSRI）抗抑郁药由于起效缓慢而受到限制，并且最近也与高发病率有关。青少年自杀率和其他副作用。尽管开发了不同系列的抗抑郁药，由于大量抑郁症患者人们对目前的现有疗法仍然难以治愈。讽刺的是，在目前的药物治疗中抑郁症，当有足够的临床和生化资料时，多巴胺能成分并未包括在内。有证据表明抑郁症有很强的多巴胺能成分。最近，三元胺摄取抑制剂（TUI）与多巴胺、血清素和去甲肾上腺素转运蛋白相互作用涉及有效的抗抑郁活性。这是因为额外的多巴胺能成分可以通过激活奖励系统中的中皮质边缘多巴胺能通路，有效缓解抑郁症。这可以起到减少快感缺乏的作用，快感缺乏与多巴胺能传递缺陷有关，是一种抑郁心理状态的核心组成部分。在我们努力发现和开发新分子的过程中与多种单胺转运蛋白相互作用，我们最近开发了不对称二胺和三胺转运蛋白取代的吡喃衍生物。对所有三种单胺转运蛋白的摄取抑制研究表明存在多样性活性取决于吡喃环或N-苄基部分上的取代的性质。这初步结果还表明这些分子与单胺转运蛋白的有效相互作用主要表现在（-）-异构体中。三种不同这些研究中出现的分子类别，它们被标记为血清素-去甲肾上腺素再摄取抑制剂（SNRI）、NRI 和三重再摄取抑制剂（TUI）。 TUI 的主要分子之一 (-)-17a，表现出有效的去甲肾上腺素和血清素抑制（Ki；分别为 5.09 和 37.7 nM）活性以及适度的多巴胺转运蛋白摄取抑制活性（Ki；85 nM），在不同的体内进一步评估抑郁症动物模型研究。体内结果表明 (-)-17a 可以有效减少大鼠的不动性强迫游泳试验和小鼠悬尾试验。此外，运动活动结果表明，这不动的减少不是由于运动激活所致。我们现在计划跟进我们的初步工作对这些吡喃衍生物进行 SAR 研究，以开发更合适的 TUI 先导分子。铅化合物与将在动物实验中评估合适的抗抑郁特性。最强的两个将测试抗抑郁分子的抗焦虑作用以及脑源性表达神经营养因子（BDNF），与抗抑郁药物的临床作用有关。