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
• 负责人: Aloke K Dutta
• 金额: $ 40.33万
• 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/7728202
• 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; 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; 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; depressed; depression; 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）： 严重抑郁症是一个严重的健康问题，抑郁症被认为是世界上第二大使人衰弱的疾病，仅次于心血管疾病。选择性血清素再摄取抑制剂（SSRIs）抗抑郁药由于起效缓慢而受到限制，并且最近还与青少年高自杀率和其他副作用有关。尽管开发了不同系列的抗抑郁药，但仍然存在对进一步改进的治疗的显着未满足的需求，因为大量抑郁症患者仍然对当前的现有疗法难以治疗。具有讽刺意味的是，在目前的抑郁症药物治疗中，当有大量临床和生化证据表明抑郁症存在强多巴胺能成分时，却没有包括多巴胺能成分。最近，三重单胺摄取抑制剂（TUI）与多巴胺、血清素和去甲肾上腺素转运蛋白相互作用，被认为具有有效的抗抑郁活性。这是因为额外的多巴胺能成分可以通过激活奖赏系统中的中皮质边缘多巴胺能通路来有效缓解抑郁症。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，是抑郁精神状态的核心组成部分。在我们努力发现和开发与多种单胺转运蛋白相互作用的新型分子的过程中，我们最近开发了不对称二取代和三取代吡喃衍生物。对所有三种单胺转运蛋白的摄取抑制研究表明，根据吡喃环或 N-苄基部分的取代性质，具有多种活性。初步结果还表明这些分子与单胺转运蛋白相互作用的立体特异性要求，因为有效的相互作用主要表现在(-)-异构体中。这些研究中出现了三类不同的分子，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）。主要 TUI 分子之一 (-)-17a 表现出有效的去甲肾上腺素和血清素抑制活性（Ki；分别为 5.09 和 37.7 nM）以及适度的多巴胺转运蛋白摄取抑制活性（Ki；85 nM），在不同的体内抑郁症动物模型研究中进行了进一步评估。体内结果表明，(-)-17a 可以有效减少大鼠强迫游泳试验和小鼠悬尾试验中的不动。此外，运动活动结果表明，这种不动性的减少并不是由于运动激活所致。我们现在计划跟进对这些吡喃衍生物的初步 SAR 研究，以开发更合适的 TUI 先导分子。具有合适特性的先导化合物将在动物实验中评估其抗抑郁特性。将测试两种最有效的抗抑郁分子的抗焦虑作用以及与抗抑郁药物的临床作用有关的脑源性神经营养因子（BDNF）的表达。公共卫生相关性：重度抑郁症是一个严重的健康问题，仅次于心血管疾病，抑郁症被认为是世界上第二大使人衰弱的疾病。单相抑郁症在所有其他躯体和精神疾病之前排名第一。据信，至少 20% 的人一生中至少患有一次抑郁症。抑郁症可能致命，因为大多数患者认为危及生命的行为和自杀。目前对抑郁症的治疗远不理想，因为许多患有抑郁症的患者尽管接受了强化治疗，但仍然有症状。最近的一项研究和其他观察结果表明，大多数在抑郁症诊所就诊的患者在使用现有抗抑郁药物后并未获得完全缓解。该提案解决了当前抗抑郁治疗中缺失的关键成分之一，即多巴胺在抑郁症中的作用。在本申请中假设，与仅针对血清素和去甲肾上腺素系统的抗抑郁药相比，以校准方式掺入的具有三元单胺摄取抑制活性的分子将提供更有效的抗抑郁作用。