Discovery of non-addictive KOR antagonists for migraine prophylaxis

 描述（由申请人提供）：偏头痛是世界上最常见的神经系统疾病。这种情况的特点是由许多阶段，包括前驱症状，头痛阶段和后期症状。在头痛阶段，发生致残性头痛，通常是单侧的，持续4 - 72小时。偏头痛发作还经常伴随恶心、呕吐和对包括光和声音在内的各种外部刺激的超敏反应。国际头痛协会将偏头痛分为无先兆偏头痛（MO）和有先兆偏头痛（MA）。偏头痛的病理生理学尚未完全了解，但最终，偏头痛被认为是由能够激活遗传易感个体中的三叉神经血管系统的改变的皮质兴奋性（兴奋障碍）的状态引起的。偏头痛最常见的临床诱因之一是压力。压力如何引发偏头痛尚不清楚。最近的证据表明，压力激活强啡肽/KOR系统，产生多种CNS效应。我们的初步数据表明，压力可以诱导的功能是一致的偏头痛的临床观察，在一个新的动物模型药物过度使用头痛（MOH）引起的一段时间暴露于曲坦类药物。在这个提议中，我们计划发现一种脑渗透性κ阿片受体（KOR）拮抗剂，可以开发用于预防性治疗偏头痛。我们将从初步的支架合成和优化化合物，在体外表征它们的受体选择性，并在体内评估它们的药效学（PD），药代动力学（PK），代谢，副作用和安全性。第一个具体目标是合成并进行新型4-胺-N-（喹啉-2-基）哌啶的体外测定。第二个具体目标将评估这些新化合物的DMPK特征。目标3将在我们的大鼠MOH模型中表征CYM51317（原型KOR拮抗剂）在偏头痛预防中的作用，并筛选用于偏头痛预防的新型KOR拮抗剂，以鉴定具有药物样特征的新分子，从而能够进行IND申报。这些研究将允许鉴定可用于人类评价的候选分子。

 DESCRIPTION (provided by applicant): Migraine is the world's most common neurological disorder. This condition is characterized by a number of phases including a prodrome, the headache phase and a post-drome. In the headache phase, disabling cephalic pain occurs that is typically unilateral and persists for 4-72 hours. The migraine attack is also often associated with nausea, vomiting and hypersensitivity to a variety of external stimuli including light and sound. The International Headache Society distinguishes migraine without aura (MO) and migraine with aura (MA). The pathophysiology of migraine is not well understood but ultimately, migraine is believed to arise from a state of altered cortical excitability (dysexcitability) capabe of activating the trigeminovascular system in genetically susceptible individuals. One of the most commonly noted clinical triggers of migraine is stress. How stress may trigger migraine is unknown. Recent evidence suggests that stress activates the dynorphin/KOR system to produce multiple CNS effects. Our preliminary data suggest that stress can induce features that are consistent with clinical observations of migraine in a novel animal model of medication overuse headache (MOH) induced by a period of exposure to triptan drugs. In this proposal, we plan to discover a brain penetrant kappa opioid receptor (KOR) antagonist that can be developed for the prophylactic treatment of migraine. We will synthesize and optimize compounds from a preliminary scaffold, characterize them in vitro for their receptor selectivity, and evaluate them for harmacodynamics (PD), pharmacokinetic (PK), metabolic, side-effect and safety profiles in vivo. The first specific aim will synthesize and perform in vitro assays of novel 4-amine-N-(quinolyn-2- yl)piperidines. The second specific aim will assess the DMPK characteristics of these novel compounds. Aim 3 will characterize CYM51317, a prototype KOR antagonist, in migraine prevention in our rat MOH model and screen novel KOR antagonists for migraine prophylaxis to identify new molecules that have drug-like profiles that will enable IND-filing. These studies will allow identification of a candidate molecule that can be pursued for human evaluation.