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
• 负责人: Aloke K Dutta
• 金额: $ 39.03万
• 依托单位: WAYNE STATE UNIVERSITY
• 依托单位国家: 美国
• 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/7885638
• 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; Hand; 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; public health relevance; research study; response; reuptake; suicidal act; suicide rate; tool; transmission process; uptake

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Major depression disorder is a significant health problem and behind cardiovascular disease, depression is considered the second most debilitating disease in the world. Unipolar depression is ranked as number one before all other somatic and psychiatric illnesses. It is believed that at least 20% of all individual suffer from a depressive episode at least once in their lifetime. Depression is potentially fatal since most sufferers consider life threatening acts and suicide. Current therapy for depression is far less than ideal, as many patients suffering from depression remain symptomatic in spite of intensive treatment. In a recent study and from other observations, it has been demonstrated that majority of patient enrolled in a depression clinics did not attain full remission with existing antidepressants. This proposal addresses one of the key missing components in the current antidepressant therapy, which is the role of dopamine in depression. It is hypothesized in this application that molecules with triple monoamine uptake inhibitory activity incorporated in a calibrated way will provide more effective antidepressant action compared to antidepressants targeting only serotonin and norepinephrine systems.

描述（由申请人提供）：严重抑郁症是一个重大的健康问题，在心血管疾病后面，抑郁症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，最近也与青少年自杀率和其他副作用有关。尽管有不同阵列的抗抑郁药的发展，但仍然需要更高的改进治疗，因为大量沮丧的人仍然对当前现有的疗法难治。具有讽刺意味的是，在当前的抑郁症药物治疗中，当有足够的临床和生化证据表明抑郁症中有强大的多巴胺能成分时，多巴胺能成分尚未包括在内。最近，与多巴胺，5-羟色胺和去甲肾上腺素转运蛋白相互作用的三胺摄取抑制剂（TUI）已与有效的抗抑郁活性有关。这是由于以下事实：额外的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。这可以减少Anhedonia，这与多巴胺能传播的不足有关，并且是抑郁状态的核心组成部分。为了发现和开发与多个单胺转运蛋白相互作用的新型分子，我们最近开发了不对称的二 - 替代pyran衍生物。对所有三种单胺转运蛋白的摄取抑制作用研究表明，根据pyran环上的取代的性质或N-苯唑部分的替代性质。初步结果还表明，这些分子与单胺转运蛋白的相互作用的立体特异性要求，因为有效的相互作用主要在（ - ） - 异构体中表现出来。这些研究中出现了三种不同类别的分子，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，表现出有效的去甲肾上腺素和5-羟色胺抑制（分别为Ki; 5.09和37.7 nm），以及在不同的多巴胺转运蛋白转运蛋白抑制活性（Ki; 85 Nm）中，在不同的VIV抑制动物模型研究中进一步评估。体内结果表明（ - ）-17A可以有效地减少大鼠强迫泳测试和小鼠尾悬架测试的固定性。此外，运动活性结果表明，这种固定性的降低不是由于运动激活。现在，我们计划跟进我们对这些pyan衍生物的初步研究，以开发更合适的TUI铅分子。在动物实验中，将评估具有合适特性的铅化合物的抗抑郁特性。将测试两个最有效的抗抑郁药分子的抗焦虑作用，以及脑衍生的神经营养因子（BDNF）的表达，与抗抑郁药的临床作用有关。公共卫生相关性：严重抑郁症是一个重大的健康问题，在心血管疾病背后，抑郁症被认为是世界上第二大衰弱的疾病。单极抑郁症在所有其他躯体和精神病疾病之前被排名第一。人们认为，至少有20％的人一生中至少遭受一次抑郁症的痛苦。抑郁症可能是致命的，因为大多数患者都认为威胁生命的行为和自杀。目前对抑郁症的治疗远非理想，因为许多患有抑郁症的患者尽管接受了强化治疗，但仍有症状。在最近的一项研究和其他观察结果中，已经证明，在抑郁症诊所入学的大多数患者并未获得现有抗抑郁药的完全缓解。该提案介绍了当前抗抑郁药疗法中的主要缺失成分之一，这是多巴胺在抑郁症中的作用。在该应用中假设，与仅针对仅针对5-羟色胺和去甲肾上腺素系统的抗抑郁药相比，以校准方式纳入三倍单胺抑制活性的分子将提供更有效的抗抑郁药。