Novel Triple Uptake Inhibitors for Treatment of Depression

描述(申请人提供)：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。选择性5-羟色胺再摄取抑制剂(SSRIs)抗抑郁药起效慢，最近还被认为与青少年高自杀率和其他副作用有关。尽管开发了不同种类的抗抑郁药物，但由于大量抑郁症患者仍然对现有的治疗方法无效，因此仍有大量的需求尚未得到满足，需要更多的改进治疗。具有讽刺意味的是，在目前的抑郁症药物治疗中，当有充分的临床和生化证据表明抑郁症中存在较强的多巴胺能成分时，并未包括多巴胺能成分。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重单胺摄取抑制剂(TUI)被认为具有强大的抗抑郁活性。这是由于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有效地缓解抑郁。这可以起到减少快感缺失的作用，快感缺失与多巴胺能传递障碍有关，是抑郁心理状态的中心组成部分。在我们努力发现和开发与多个单胺转运体相互作用的新分子的过程中，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体的摄取抑制研究表明，不同的活性取决于吡喃环或N-苄基部分上取代的性质。初步结果还表明，这些分子与单胺转运体的相互作用需要立体特异性，因为强烈的相互作用主要表现在(-)-异构体中。从这些研究中出现了三类不同的分子，它们被标记为5-羟色胺-去甲肾上腺素再摄取抑制剂(SNRI)、NRI和三重再摄取抑制剂(TUI)。其中一个主要的TUI分子，(-)-17a，显示出强大的去甲肾上腺素和5-羟色胺抑制活性(Ki；分别为5.09和37.7 nM)以及适度的多巴胺转运体摄取抑制活性(Ki；85 nM)，在不同的体内抑郁动物模型研究中进一步进行了评估。体内实验结果表明，(-)-17a能有效降低大鼠强迫游泳实验和小鼠悬尾实验中的不动。此外，运动活动结果表明，这种不动能力的减少不是由于运动激活。我们现在计划跟进我们对这些吡喃衍生物的初步SAR研究，以开发更合适的TUI铅分子。具有合适性能的先导化合物将在动物实验中评估其抗抑郁性能。两个最有效的抗抑郁分子将被测试其抗焦虑作用，以及脑源性神经营养因子(BDNF)的表达，这与抗抑郁药物的临床作用有关。公共卫生相关性：抑郁症是一个重大的健康问题，仅次于心血管疾病，抑郁症被认为是世界上第二大最令人衰弱的疾病。单相抑郁是排在所有其他躯体和精神疾病之前的第一位。据信，至少20%的人一生中至少有一次抑郁发作。抑郁症可能是致命的，因为大多数患者认为威胁生命的行为和自杀。目前对抑郁症的治疗远不理想，因为许多抑郁症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中，已经证明在抑郁症诊所登记的大多数患者并没有通过现有的抗抑郁药物获得完全缓解。这项建议解决了目前抗抑郁治疗中缺失的关键组成部分之一，即多巴胺在抑郁中的作用。在这一应用中假设，与仅针对5-羟色胺和去甲肾上腺素系统的抗抑郁药相比，以校准方式加入具有三重单胺摄取抑制活性的分子将提供更有效的抗抑郁作用。

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.