Novel Triple Uptake Inhibitors for Treatment of Depression

阿洛克·K·杜塔 严重的抑郁症是一个重大的健康问题，在心血管疾病的背后，抑郁症 被认为是世界上第二大令人衰弱的疾病。选择性5-羟色胺再摄取抑制剂(SSRIs) 抗抑郁药物一直受到起效缓慢的限制，而且最近也被认为与高血压有关。 青少年自杀率和其他副作用。尽管开发了不同种类的抗抑郁药， 仍然有大量的需求没有得到满足，需要更好的治疗，因为大量的抑郁症患者 人们仍然对目前的现有疗法难以接受。讽刺的是，在目前的药物治疗中 抑郁症，多巴胺能成分没有包括在内，当有足够的临床和生化 有证据表明抑郁症中有很强的多巴胺能成分。最近，三重单胺 摄取抑制物(TUI)与多巴胺、5-羟色胺和去甲肾上腺素转运体相互作用 牵涉到了强大的抗抑郁活性。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。 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障碍有关，是一种 抑郁的精神状态的核心成分。在我们努力发现和开发新的分子以 与多个单胺转运体相互作用，我们最近开发了不对称二和三- 取代的吡喃衍生物。对所有三种单胺转运体的摄取抑制研究表明 活性的大小取决于吡喃环或N-苄基上取代的性质。这个 初步结果还表明，这些分子与分子相互作用需要立体特异性。 作为强相互作用的单胺转运体主要存在于(-)-异构体中。三种不同的 从这些研究中产生了几类分子，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)。一种前导TUI分子，(-)-17a，表现出 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)，在不同的体内进一步评估 抑郁症动物模型研究。体内实验结果表明，(-)-17a可有效减少大鼠的不动 强迫游泳试验和小鼠悬尾试验。此外，运动活动结果表明，这 不动能力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选 合成孔径雷达对这些吡喃衍生物进行研究，以开发更适合的TUI铅分子。先导化合物与 将在动物实验中评估抗抑郁特性的合适特性。两个最有力的 抗抑郁分子将被测试其抗焦虑的效果，以及对大脑来源的表达的影响 神经营养因子(BDNF)，参与抗抑郁药物的临床作用。

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.