Piperidine-Based Compounds as Therapeutics for Narcolepsy-Cataplexy

据估计，睡眠剥夺和睡眠障碍每年给美国人造成的生产力损失、医疗费用、病假以及财产和环境损害超过1000亿美元。嗜睡症是一种致残性疾病，也是了解其他睡眠障碍的关键。紧张症是发作性睡病的另一个主要衰弱症状，估计影响60 - 90%的发作性睡病患者。自从发现莫达非尼强大的促醒作用以来的二十年里，莫达非尼已成为治疗嗜睡症和其他睡眠障碍中过度嗜睡的最广泛使用的处方药。尽管莫达非尼具有强大的促醒作用，但它不能抑制震颤。莫达非尼的这一缺点可能源于其在去甲肾上腺素转运蛋白上缺乏活性，去甲肾上腺素转运蛋白是几种强效降压药的作用部位。结构上与莫达非尼相关，但在去甲肾上腺素转运蛋白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已经建立了一个化合物库的诺氟沙星/莫达非尼杂合配体，作为选择性单胺转运抑制剂。这些化合物作为细胞膜多巴胺、去甲肾上腺素和5-羟色胺转运蛋白（DAT、NET和SERT）抑制剂的效力各不相同。这些新化合物中的一些是有效的特异性DAT抑制剂，而另一些则以大致相等的效力抑制DAT和NET。这些混合化合物的不同药理学特征为嗜睡症和一般睡眠/觉醒障碍的药理学研究提供了强大的资源。通过这笔赠款的资助，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，以寻求新型选择性单胺转运蛋白抑制剂作为过度嗜睡和嗜睡症的潜在治疗药物。本研究的具体目标是：1。基于手中的化合物库，12个有效的反式哌啶配体具有适当的DAT和NET的选择性配置文件将被重新合成。此外，还将合成这些选定化合物的顺式非对映体，并研究其单胺转运蛋白抑制活性。2.将在下丘脑泌素/共济失调蛋白-3（hcrt/atax）小鼠中在行为和脑电图水平上测量那些表现出良好选择性的所选化合物对睡眠发作和紧张症的抑制的剂量-反应曲线。3.将对那些显示出最有希望作为过度嗜睡和发作性睡病-昏厥的潜在治疗剂的化合物进行临床前ADMET研究，如目的2所确定的。 公共卫生相关性：Acenta Discovery开发了一种基于哌啶的诺氟沙星/莫达非尼杂合配体的化合物库，可作为选择性单胺转运蛋白抑制剂。这些杂合化合物的不同药理学特征为研究发作性睡病和一般睡眠/觉醒障碍的药理学以及过度嗜睡和发作性睡病的潜在治疗提供了强大的资源。

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.