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.

杜塔（Aloke K）重度抑郁症是一个重大的健康问题，在心血管疾病背后，抑郁症是被认为是世界上第二大衰弱的疾病。选择性5-羟色胺再摄取抑制剂（SSRIS）抗抑郁药受到缓慢发作的限制，最近也涉及到高青少年自杀率和其他副作用。尽管有不同阵列的抗抑郁药的发展，但由于大量抑郁症人们仍然对当前现有疗法难治。具有讽刺意味的是，在当前的药物治疗抑郁症，多巴胺能成分在有足够的临床和生化时尚未包括在内证据表明抑郁症中强烈的多巴胺能成分。最近，三倍单胺与多巴胺，5-羟色胺和去甲肾上腺素转运蛋白相互作用的摄取抑制剂（TUI）已经与有效的抗抑郁活性有关。这是由于以下事实：其他多巴胺能成分可以通过激活奖励系统中的中皮质胶菌多巴胺能途径来有效缓解抑郁症。这可以降低Anhedonia，这与多巴胺能传播的不足有关，并且是抑郁状态的中心部分。为了发现和开发新的分子与多种单胺转运蛋白的相互作用，我们最近发展取代的pyran衍生物。所有三种单胺转运蛋白的摄取抑制研究均表明多样性根据pyran环上的取代或N-苄基部分的替代性质。这初步结果还表明，这些分子与这些分子相互作用的立体特异性要求单胺转运蛋白作为有效的相互作用主要在（ - ） - 异构体中表现出来。三个不同从这些研究中出现的分子类别，它们被标记为5-羟色胺 - 肾上腺素再摄取抑制剂（SNRI），NRI和三重再摄取抑制剂（TUI）。 TUI分子之一，（ - ） - 17a，展示有效的去甲肾上腺素和5-羟色胺抑制（Ki; 5.09和37.7 nm）以及多巴胺转运蛋白转运蛋白抑制活性（Ki; 85 nm）在不同的体内进一步评估抑郁动物模型研究。体内结果指示（ - ） - 17a可以有效降低大鼠的固定性强迫游泳测试和小鼠尾悬架测试。此外，运动活性结果表明固定性的降低不是由于运动激活。我们现在计划跟进我们的初步 SAR对这些pyran衍生物的研究以开发更合适的TUI铅分子。铅化合物在动物实验中，将评估合适的特性的抗抑郁特性。两个最有力的将测试抗抑郁药的抗焦虑作用，并对脑的表达进行测试神经营养因子（BDNF），涉及抗抑郁药的临床作用。