Piperidine-Based Compounds as Therapeutics for Narcolepsy-Cataplexy

描述(由申请人提供)：据估计，睡眠不足和睡眠障碍每年给美国人造成的生产力损失、医疗费用、病假、财产和环境破坏超过1000亿美元。嗜睡症是一种致残性疾病，也是理解其他睡眠障碍的关键。猝倒是发作性睡病的另一个主要衰弱症状，据估计，60%到90%的发作性睡病患者会受到影响。在发现莫达非尼强大的促醒作用后的20年里，莫达非尼已成为治疗发作性睡病和其他睡眠障碍中过度嗜睡的最广泛使用的处方药。尽管莫达非尼有很强的促醒作用，但它并不能抑制猝倒。莫达非尼的这种缺点可能源于它在去甲肾上腺素转运体上缺乏活性，去甲肾上腺素转运体是几种有效的猝倒疗法的作用部位。在结构上与莫达非尼相关，但在去甲肾上腺素转运体抑制方面表现出新的药理学特征的化合物，可能比莫达非尼本身具有更大的治疗价值。Acenta已经建立了一个诺卡因/莫达非尼杂化配体的化合物库，作为选择性单胺转运体抑制剂。这些化合物作为细胞膜多巴胺、去甲肾上腺素和5-羟色胺转运体(DAT、NET和SERT)的抑制剂的效力各不相同。其中一些新化合物是有效的、特异的DAT抑制剂，而另一些化合物则以大致相同的效力同时抑制DAT和Net。这些混合化合物的不同药理学特征为研究发作性睡病和睡眠/觉醒障碍的药理学提供了强大的资源。通过这笔赠款的资金，我们打算跟进我们取得的令人兴奋的初步发现，具体目标如下：寻求新型选择性单胺转运体抑制剂，作为过度嗜睡和发作性睡病-猝倒的潜在疗法。本研究计划的具体目标是：1.在现有化合物文库的基础上，重新合成12个具有合适的DAT和Net选择性图谱的有效反式-哌啶配体。此外，还将合成这些选定化合物的顺式非对映异构体，并研究它们的单胺转运体抑制活性。2.对筛选出的选择性较好的化合物进行量效曲线测定，在行为和脑电水平上抑制下丘脑型/阿塔克星(hcrt/atax)小鼠的睡眠发作和猝倒。3.将对目标2中确定的最有希望作为过度嗜睡和发作性睡病-晕厥潜在疗法的化合物进行临床前ADMET研究。 公共卫生相关性：Acenta Discovery公司开发了一个基于哌啶的诺卡因/莫达非尼杂化配体的化合物文库，作为选择性单胺转运体抑制剂。这些杂化化合物的不同药理特性为研究发作性睡病和睡眠/觉醒障碍的药理学，以及治疗过度嗜睡和发作性睡病-猝倒的潜在疗法提供了强大的资源。

DESCRIPTION (provided by applicant): Sleep deprivation and sleep disorders are estimated to cost Americans over $100 billion annually in lost productivity, medical expenses, sick leave, and property and environmental damage. Narcolepsy is a disabling illness and a key to understanding other sleep disorders. Cataplexy is another major debilitating symptom of narcolepsy, and is estimated to affect 60 to 90% of narcoleptic patients. In the two decades since the discovery of its robust wake-promoting effect, modafinil has become the most widely used prescription drug for treatment of excessive sleepiness in narcolepsy and other sleep disorders. Its robust wake-promoting effect notwithstanding, modafinil fails to suppress cataplexy. This disadvantage of modafinil likely stems from its lack of activity at the norepinephrine transporter, the site of action for several potent cataplexy therapeutics. Compounds that are structurally related to modafinil, but exhibit novel pharmacological profiles with respect to norepinephrine transporter inhibition, may be of greater therapeutic value than modafinil itself. Acenta has established a compound library of nocaine/modafinil hybrid ligands that act as selective monoamine transporter inhibitors. The compounds vary in their potency as inhibitors of the cell membrane dopamine, norepinephrine and serotonin transporters (DAT, NET and SERT). Some of these novel compounds are potent, specific DAT inhibitors, while some others inhibit both DAT and NET with roughly equal potency. The diverse pharmacological profiles of these hybrid compounds provide a powerful resource for studies on the pharmacology of narcolepsy and of sleep/wake disorders in general. Through funding from this grant, we intend to follow-up on the exciting preliminary findings we have made with the following specific aims in pursuit of novel selective monoamine transporter inhibitors as potential therapeutics for excessive sleepiness and narcolepsy-cataplexy. The specific aims of this research proposal are: 1. Based on the compound library in hand, 12 potent trans-piperidine ligands possessing appropriate DAT and NET selectivity profiles will be resynthesized. Additionally, the cis-diastereomers of these selected compounds will also be synthesized and their monoamine transporter inhibitory activity will be investigated. 2. The dose-response curves of those selected compounds that exhibit good selectivity will be measured for the suppression of sleep attacks and cataplexy at the behavioral and electroencephalographic levels in hypocretin/ataxin-3 (hcrt/atax) mice. 3. Pre-clinical ADMET studies will be carried out on those compounds showing the greatest promise as potential therapeutics for excessive sleepiness and narcolepsy-cataplexy as determined in Aim 2. Public Health Relevance: Acenta Discovery has developed a compound library of piperidine-based nocaine/modafinil hybrid ligands that act as selective monoamine transporter inhibitors. The diverse pharmacological profiles of these hybrid compounds provide a powerful resource for studies on the pharmacology of narcolepsy and of sleep/wake disorders in general and the potential therapeutics for excessive sleepiness and narcolepsy-cataplexy.