Orexin receptor antagonists for drug addiction and panic disorder

描述（由申请人提供）：本申请是响应RFA-NS-13-003， NIH神经科学研究蓝图重大挑战：发现神经系统疾病的新药（U01）。食欲素- A （OXA）和食欲素- b (OXB)，也称为下丘脑分泌素-1和下丘脑分泌素-2，是刺激食欲素-1 （OX1）和食欲素-2 （OX2）受体的下丘脑外侧神经肽。最近，我们的实验室和其他人已经产生了令人信服的证据，证明OXA肽通过OX1受体作用，调节尼古丁对大脑奖励系统的刺激作用，从而控制大鼠和小鼠的尼古丁自我给药行为。此外，OX1受体调节戒断大鼠和小鼠中已消失的药物寻求反应的复发样恢复。事实上，开发可安全用于人类的OX1受体拮抗剂被认为可能是开发治疗人类烟草依赖和其他物质滥用障碍的新型治疗药物的最有希望的方法。我们的目标是通过Blueprint神经治疗网络促进新型OX1受体拮抗剂的设计、合成和相关临床前模型的测试。我们已经确定了新的化学支架，可以产生选择性的OX1受体拮抗剂，应该适合通过蓝图网络开发。我们已经开发了可靠的基于细胞的OX1受体拮抗剂作用（和适当的反筛）检测方法。此外，我们建立了目前可用的最相关的尼古丁成瘾动物模型，即小鼠静脉内尼古丁自我给药程序。我们现在可以评估新型OX1受体拮抗剂对野生型小鼠尼古丁强化的影响，以确定这些化合物是否在体内表现出功效。此外，可以评估新型OX1受体拮抗剂对OX1受体敲除小鼠尼古丁反应的影响，从而确定这些化合物是否具有行为选择性。这个令人兴奋的药物开发项目利用了Blueprint神经治疗网络的独特能力。它将利用我们迄今为止在鉴定新型化学支架方面的进展，并利用我们高度相关的体外和体内分析。因此，该项目有望产生OX1受体拮抗剂作为戒烟的新疗法。

DESCRIPTION (provided by applicant): This application is in response to RFA-NS-13-003, NIH Blueprint for Neuroscience Research Grand Challenge: Discovering Novel Drugs for Disorders of the Nervous System (U01). Orexin- A (OXA) and orexin-B (OXB), also known as hypocretin-1 and hypocretin-2, are lateral hypothalamic (LH) neuropeptides that stimulate orexin-1 (OX1) and orexin-2 (OX2) receptors. Recently, our laboratory and others have generated compelling evidence that OXA peptide, acting through OX1 receptors, regulates the stimulatory effects of nicotine on brain reward systems and thereby controls nicotine self-administration behavior in rats and mice. In addition, OX1 receptors regulate the relapse-like reinstatement of extinguished drug-seeking responses in abstinent rats and mice. Indeed, the development of OX1 receptor antagonists that are safe for use in humans is considered perhaps the most promising approach to developing novel therapeutic agents for tobacco dependence and other substance abuse disorders in humans. We aim to facilitate the design, synthesis and testing in relevant preclinical models, of novel OX1 receptor antagonists through the Blueprint Neurotherapeutics Network. We have identified novel chemical scaffolds that are yielding selective OX1 receptor antagonists that should be suitable for development through the Blueprint Network. We have developed robust cell-based assays to reliably OX1 receptor antagonist actions (and appropriate counterscreens). In addition, we have established the most relevant animal model of nicotine addiction currently available, the intravenous nicotine self-administration procedure, in mice. We can now assess the effects of novel OX1 receptor antagonists on nicotine reinforcement in wildtype mice to determine if the compounds demonstrate in vivo efficacy. Also, the effects of novel OX1 receptor antagonists on responding for nicotine in OX1 receptor knockout mice can be assessed, thereby determining if the compounds are behaviorally selective. This exciting drug development program capitalizes on the unique capabilities of Blueprint Neurotherapeutics Network. It will leverage our progress to date in identifying novel chemical scaffolds and take advantage of our highly relevant in vitro and in vivo assays. Hence, this program promises to yield OX1 receptor antagonists as novel therapeutic for smoking cessation.