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: 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
• 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

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.

阿洛克？杜塔 严重抑郁症是一个重要的健康问题，在心血管疾病的背后，抑郁症是 它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） 抗抑郁药由于起效缓慢而受到限制，最近还涉及高剂量抗抑郁药。 青少年自杀率和其他副作用。尽管抗抑郁药的不同阵列的发展， 仍然存在对更好的治疗的显著未满足的需求，因为大量的抑郁症患者 人们仍然对目前现有的疗法难以接受。具有讽刺意味的是，在目前的药物治疗中， 抑郁症，多巴胺能成分还没有被列入时，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 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）已被 有很强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脑皮质边缘多巴胺能通路有效缓解抑郁症。 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的缺陷有关，并且是一种神经递质。 抑郁状态的核心组成部分在我们努力发现和开发新的分子， 与多种单胺转运蛋白的相互作用，我们最近开发了不对称的二和三- 取代的吡喃衍生物。所有三种单胺转运蛋白的摄取抑制研究表明， 活性取决于吡喃环或N-苄基部分上取代的性质。的 初步结果还表明，这些分子与 单胺转运蛋白的强相互作用主要表现在（-）-异构体中。三种不同 从这些研究中出现了一类分子，它们被标记为肾上腺素-去甲肾上腺素再摄取 抑制剂（SNRI）、NRI和三重再摄取抑制剂（TUI）。其中一种TUI先导分子（-）-17 a， 强效的去甲肾上腺素和5-羟色胺抑制（Ki;分别为5.09和37.7 nM）活性沿着 适度的多巴胺转运蛋白摄取抑制活性（Ki; 85 nM），在不同的体内实验中进一步评价。 抑郁症动物模型研究。体内实验结果表明，（-）-17 a可有效地降低大鼠的不动性 强迫游泳试验和小鼠悬尾试验。此外，自发活动的结果表明， 不动性的降低不是由于运动激活。我们现在计划跟进我们初步的 对这些吡喃衍生物进行SAR研究，以开发更合适的TUI先导分子。铅化合物， 将在动物实验中评价合适的抗抑郁性质。两种最有效的 将测试抗抑郁分子的抗焦虑作用，并测试其对脑源性 神经营养因子（BDNF），与抗抑郁药物的临床作用有关。