Development of Nociceptin Receptor Agonists for Post-Traumatic Stress Disorder

总结 创伤后应激障碍（PTSD）是一种高度痛苦和潜在的残疾条件，涉及改变 某些个体在经历了严重创伤性事件后产生的恐惧学习。虽然通用 抗抑郁药和短期抗焦虑药是PTSD治疗的主要药物，这些药物仍然存在。 不足以治疗疾病。因此，仍然存在大量未满足的医学需求来开发用于治疗癌症的新疗法。 PTSD和其他恐惧相关疾病。在我们之前发表的研究中，在一组1847名PTSD患者中， 在有重大终身创伤史的患者中，我们发现单核苷酸多态性（SNP） 在编码伤害感受素受体（NOP-R）的基因中，与PTSD症状的增加有关。我们 还发现该SNP与恐惧泛化和杏仁核功能增强有关 连通性。使用一个恐惧失调的小鼠模型，我们发现oprl 1基因的表达发生了改变， （编码NOP-R）。全身和中央杏仁核灌注SR-8993，我们的高度 选择性NOP-R激动剂，受损的恐惧记忆巩固，表明NOP-R与恐惧有关 处理和创伤后应激障碍症状我们的数据还表明NOP-R的激活会干扰恐惧 记忆巩固，甚至在创伤性事件后对创伤后应激障碍的治疗有影响。 该项目的具体目标是开发有用的NOP-R调节剂，以了解NOP-R的生物学特性。 着眼于最终的临床应用。我们在以前的努力中开发的化合物， 由于NOP-R相对于其他类似物的前所未有的选择性， 阿片受体，特别是μ阿片受体（莫尔）。NOP-R相对于μ受体的选择性是 降低成瘾可能性和避免与莫尔相关的不必要的副作用 活化，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的选择性高于对莫尔的选择性，继续具有显著的莫尔激动剂 活动，一个功能，我们的目的是纠正这项拟议的工作。为了支持我们的方法的可行性， 我们展示了对NOP-R的选择性超过莫尔10，000倍的未公开化合物。额外 化学方面的努力将旨在改善优选先导化合物的药物样特征， 药代动力学（PK）特性（目的1）。药理学特征分析将包括NOP-R和 阿片受体功能，进一步评估DMPK参数，以确保体内效用的潜力 (Aim 2）。PTSD样动物模型将用于评估靶点-暴露关系，以及一组体内 神经行为和成瘾潜力评估将用于确定潜在的不希望的 效果（目标3）。我们的目标是提供一套临床前验证，安全，高选择性，脑渗透小 一种有效的减轻PTSD样恐惧和焦虑行为的分子痛敏素受体激动剂， 创伤后应激障碍模型，准备用于临床转化。

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.