Development of Nociceptin Receptor Agonists for Post-Traumatic Stress Disorder

摘要 创伤后应激障碍(PTSD)是一种非常令人痛苦和可能致残的情况，涉及到 一些人在经历了高度创伤的事件后会害怕学习。虽然是通用的 抗抑郁药物和短期抗焦虑药物是创伤后应激障碍治疗的主要药物，这些药物仍然 不足以治疗这种疾病。因此，仍有大量未得到满足的医学需求需要开发新的治疗方法。 创伤后应激障碍和其他与恐惧相关的障碍。在我们之前发表的研究中，在1847名人类创伤后应激障碍的队列中 有重大终生创伤病史的患者，我们发现单核苷酸多态(SNP) 在编码伤害素受体(NOP-R)的基因中，与创伤后应激障碍症状增加有关。我们 研究还发现，这种SNP与恐惧泛化和杏仁核-脑岛功能增强有关 连通性。使用失调恐惧的小鼠模型，我们发现Oprl1基因的表达发生了变化 (编码NOP-R)在杏仁核内。全身和中央杏仁核输注SR-8993，我们的高度 选择性NOP-R激动剂，削弱恐惧记忆巩固，提示NOP-R与恐惧有关 加工和创伤后应激障碍症状。我们的数据还表明，NOP-R的激活干扰了恐惧 记忆巩固，对创伤事件后的创伤后应激障碍的治疗具有指导意义。 这个项目的具体目标是开发有用的NOP-R调节器来了解NOP-R的生物学 以期最终应用于临床。我们在以前的努力中开发的化合物，以及它们的 由于NOP-R对另一种具有前所未有的选择性，类似物最适合实现这一目标 阿片受体，特别是Mu阿片受体(MOR)。对NOP-R的选择性高于Mu受体 有必要降低成瘾潜力并避免与Mor相关的不良副作用 激活，包括呼吸抑制、便秘和瘙痒/瘙痒。然而，我们公布的线索 化合物SR-8993对NOP-R比MOR有一定的选择性，继续具有显著的MOR激动剂 活动，这是我们在这项拟议的工作中要纠正的一个特征。为了支持我们方法的可行性， 我们展示了未发表的化合物，它们对NOP-R的选择性是MOR的10,000倍以上。其他内容 化学工作的目的将是改善首选线索的类药物特性，并改进 药代动力学(PK)特性(目标1)。药理学分析将包括评估NOP-R和 阿片受体功能和DMPK参数的进一步评估以确保体内应用的可能性 (目标2)。类似创伤后应激障碍的动物模型将被用来评估目标-暴露关系，以及体内的一组 神经行为和成瘾潜力评估将被用来确定不受欢迎的可能性 效果(目标3)。我们的目标是提供一套预先经过临床验证的、安全的、高度选择性的、脑穿透性小的 分子伤害素受体激动剂减轻创伤后应激障碍样恐惧和焦虑行为 为临床翻译做好准备的创伤后应激障碍模型。

Summary Posttraumatic stress disorder (PTSD) is a highly distressing and potentially disabling condition involving altered fear learning that occurs in some individuals after exposure to highly traumatic events. While generic antidepressants and short-term anxiolytics are the mainstays of PTSD treatment, these drugs remain insufficient to treat the disease. Thus, there remains a large unmet medical need to develop novel therapies for PTSD and other fear related disorders. In our previously published work, in a cohort of 1847 human PTSD patients with a history of significant lifetime trauma, we found that a single-nucleotide polymorphism (SNP) within the gene encoding the nociceptin receptor (NOP-R) is associated with increased PTSD symptoms. We also found that this SNP is associated with fear generalization and increased amygdala-insula functional connectivity. Using a mouse model of dysregulated fear, we found altered expression of the oprl1 gene (encoding NOP-R) within the amygdala. Systemic and central amygdala infusion of SR-8993, our highly selective NOP-R agonist, impaired fear memory consolidation, suggesting that NOP-R is associated with fear processing and PTSD symptoms. Our data also suggest that activation of the NOP-R interferes with fear memory consolidation, with implications for the treatment of PTSD even after a traumatic event. The specific goal of this project is to develop useful NOP-R modulators to understand the biology of the NOP-R with a view toward eventual clinical application. The compounds we developed in previous efforts, and their analogs, are best-suited to reach this goal due to unprecedented selectivity for the NOP-R over the other opioid receptors, particularly the mu opioid receptor (MOR). Selectivity for NOP-R over the mu receptor is necessary to reduce addiction potential and avoid the unwanted side effects that are associated with MOR activation, including respiratory depression, constipation and itch/pruritus. However, our published lead compound, SR-8993, with some selectivity for NOP-R over MOR, continues to have significant MOR agonist activity, one feature that we aim to correct in this proposed work. In support of the feasibility of our approach, we show unpublished compounds that have over 10,000-fold selectivity for NOP-R over MOR. Additional chemistry efforts will be aimed at improving the drug-like characteristics of preferred leads and to improve pharmacokinetic (PK) properties (Aim 1). Pharmacological profiling will include assessments of NOP-R and opioid receptor function with further assessments of DMPK parameters to ensure the potential for in vivo utility (Aim 2). PTSD-like animal models will be used to assess target-exposure relationships, and a battery of in vivo neuro-behavioral and also addiction potential assessments will be used to determine potential for undesired effects (Aim 3). We aim to deliver a set of pre-clinically validated, safe, highly selective, brain penetrant small molecule nociceptin receptor agonists that attenuate PTSD-like fear and anxiety behavior in well-validated PTSD models that are primed for clinical translation.