Discovery of non-addictive KOR antagonists for migraine prophylaxis

发现用于预防偏头痛的非成瘾性 KOR 拮抗剂

• 批准号: 10011866
• 负责人: Lori Jean Van Orden
• 金额: $ 11.06万
• 依托单位: BLACKTHORN THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2021-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10011866
• 关键词: Acute; Adult; Affect; Amines; Amygdaloid structure; Analgesic Overuse Headaches; Animal Model; Auras; Behavior; Biological Availability; Blood; Brain; Brain region; Categories; Cell Membrane Permeability; Cephalic; Cerebrospinal Fluid; Characteristics; Chemicals; Chronic Daily Headaches; Classic Migraine; Clinical; Common Migraine; Corticotropin-Releasing Hormone; Cytochrome P450; Data; Development; Disease; Dose; Drug Kinetics; Dynorphins; Epidemic; Evaluation; Exposure to; Foundations; Frequencies; Fright; Functional disorder; Goals; Half-Life; Headache; Hour; Human; Hypersensitivity; In Vitro; Individual; Infusion procedures; International; Laboratories; Lead; Light; Link; Medical; Metabolic; Microinjections; Migraine; Modeling; Mood Disorders; Nausea and Vomiting; Nociception; Nociceptors; Non-Steroidal Anti-Inflammatory Agents; Opioid; Opioid Antagonist; Opioid Receptor; Oral; Pain; Pathway interactions; Patients; Penetration; Peptides; Pharmaceutical Preparations; Phase; Physiological; Population; Pre-Clinical Model; Preparation; Prevention; Preventive; Property; Prophylactic treatment; Quality of life; Rattus; Reporting; Rest; Safety; Sensory Thresholds; Series; Serum; Severities; Societies; Spreading Cortical Depression; Stimulus; Stress; Sumatriptan; Symptoms; System; Tactile; Testing; Therapeutic; Throbbing Headaches; Toxicity Tests; United States; allodynia; analog; biological adaptation to stress; central sensitization; cutaneous allodynia; dynorphin receptor; in vitro Assay; in vivo; iterative design; kappa opioid receptors; lead candidate; nervous system disorder; new therapeutic target; norbinaltorphimine; novel; piperidine; pre-clinical; prevent; programs; prophylactic; prototype; psychologic; public health relevance; receptor; response; scaffold; side effect; sound; stress related disorder; tissue injury; triptans

 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.

 描述(申请人提供)：偏头痛是世界上最常见的神经疾病。这种情况的特点是多个阶段，包括前驱症状，头痛阶段和后遗症。在头痛阶段，会出现典型的单侧头痛，持续4-72小时。偏头痛发作还经常伴随着恶心、呕吐和对包括光和声音在内的各种外部刺激的过敏。国际头痛协会区分无先兆偏头痛(MO)和有先兆偏头痛(MA)。偏头痛的病理生理学机制尚不清楚，但最终被认为是由于遗传易感个体的皮质兴奋性(兴奋性异常)能力的改变而引起的三叉神经血管系统的激活。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还不得而知。最近的证据表明，应激激活强啡肽/KOR系统，产生多种中枢神经系统效应。我们的初步数据表明，在一种新的药物过度使用头痛(MOH)动物模型中，应激可以诱导出与临床观察一致的特征，该模型是由一段时间的Triptan药物暴露引起的。在这项提案中，我们计划发现一种脑穿透性kappa阿片受体(KOR)拮抗剂，可以开发用于偏头痛的预防治疗。我们将从一个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动力学(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的4-胺-N-(喹啉-2-基)哌啶类化合物的体外检测。第二个具体目标将评估这些新化合物的DMPK特性。AIM 3将在我们的大鼠MOH模型中表征KOR原型拮抗剂CYM51317在偏头痛预防中的作用，并筛选用于预防偏头痛的新型KOR拮抗剂，以识别具有药物样特征的新分子，使IND备案成为可能。这些研究将允许识别可用于人类评估的候选分子。