Orexin receptor antagonists for drug addiction and panic disorder

描述（由申请人提供）：本申请是对RFA-NS-13-003，NIH神经科学研究大挑战蓝图：发现治疗神经系统疾病的新药（U 01）的回应。食欲素- A（OXA）和食欲素-B（OXB），也称为下丘脑泌素-1和下丘脑泌素-2，是刺激食欲素-1（OX 1）和食欲素-2（OX 2）受体的外侧下丘脑（LH）神经肽。最近，我们的实验室和其他实验室已经产生了令人信服的证据，表明OXA肽通过OX 1受体起作用，调节尼古丁对大脑奖赏系统的刺激作用，从而控制大鼠和小鼠的尼古丁自我给药行为。此外，OX 1受体调节戒断大鼠和小鼠中熄灭的药物寻求反应的复发样恢复。实际上，开发可安全用于人类的OX 1受体拮抗剂被认为可能是开发用于人类烟草依赖和其他物质滥用障碍的新型治疗剂的最有希望的方法。我们的目标是通过Blueprint Neurotherapeutics Network促进新型OX 1受体拮抗剂在相关临床前模型中的设计、合成和测试。我们已经确定了新的化学支架，产生选择性OX 1受体拮抗剂，应该适合通过蓝图网络的发展。我们已经开发了稳健的基于细胞的测定法，以可靠地发挥OX 1受体拮抗剂作用（和适当的反筛选）。此外，我们还建立了目前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OX 1受体拮抗剂对野生型小鼠尼古丁强化的影响，以确定化合物是否表现出体内功效。此外，可以评估新的OX 1受体拮抗剂对OX 1受体敲除小鼠中尼古丁应答的影响，从而确定化合物是否具有行为选择性。这个令人兴奋的药物开发计划利用了Blueprint Neurotherapeutics Network的独特功能。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试验。因此，该计划有望产生OX 1受体拮抗剂作为戒烟的新治疗剂。

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.