Discovering Small Molecule Biased Agonists for the Neuropeptide S Receptor

与事件或事物有关的焦虑症(如创伤后应激障碍、恐惧症) 将受益于同时缓解焦虑以及与 诱导性事件。尽管目前可用的抗焦虑药物能够治疗急性焦虑症，但已有研究表明 损害新记忆的形成。一些焦虑症的症状对急性和快速反应 作用苯二氮卓类药物(例如，惊恐障碍和广泛性焦虑的初始和短期治疗 无序)。然而，其他人，如创伤后应激障碍，具有持续性的高度侵入性症状(闪回)，这些症状是 对当前的治疗方法有抵抗力。此外，创伤后应激障碍与抑郁、自杀和吸毒有很高的共患率。 虐待，这本身就很难治疗，特别是在存在衰弱焦虑症的情况下。一个 选择性药物治疗既能减少治疗过程中的焦虑，又能增强记忆 缺乏。神经肽S系统有一个内源性配体(NP)和一个受体(NPSR)。 表达是相对受限的。NPS系统的治疗潜力在于其独特的行为 配置文件，这与大多数系统不同。在小鼠体内集中注射NPS可增强学习能力， 提高觉醒，产生类似焦虑的效果。发现小分子NPSR激动剂，更不用说 有偏见的激动剂一直是极其困难的。据我们所知，还没有小分子激动剂 在专利或同行评议文献中披露。根据我们实验室进行的研究，我们已经确定 第一个也是唯一一个有偏向的、小分子的NPS支架，在钙中保持完全的激动剂特性 动员试验，但减弱了提高cAMP水平的能力。这与天然多肽不同。 (NPS)，对两个第二信使通路显示大致相同的效果。我们的一个有偏见的激动者 在小鼠身上产生与NPS类似的缓解焦虑和增强记忆的作用，并可被rti-118a阻断 强大的NPS拮抗者。基于这一数据，我们假设神经肽S受体的偏向激动剂 缺乏cAMP激活的(NPSR)将有助于治疗创伤后应激障碍和其他焦虑障碍 晋升是有益的。此应用程序的化学组件旨在提高NPSR效力、维护 信号偏向，并增强先导化合物的类药物特性。的行为组件 应用程序将专注于进一步建立我们有偏见的激动剂的行为特征。这些目标将是 通过化学、体外药理学和行为药理学的合作完成 程序。

Anxiety disorders that are linked to events or things (e.g. post-traumatic stress disorder (PTSD), phobias) would benefit from the simultaneous mitigation of the anxiety as well as the memories associated with the inducing event. Although currently available anxiolytics are able to treat acute anxiety, they have been shown to impair the formation of new memories. The symptoms of some anxiety disorders respond to acute and fast acting benzodiazepines (e.g. initial and short-term treatment of panic disorder and generalized anxiety disorder). However, others, such as PTSD, have persistent, highly intrusive symptoms (flashbacks) that are resistant to current treatments. Moreover, PTSD has high comorbidity with depression, suicide, and drug abuse, which are themselves difficult to treat especially in the presence of a debilitating anxiety disorder. A selective pharmacotherapy that can both reduce anxiety within therapy sessions and is memory enhancing is lacking. The neuropeptide S system has one endogenous ligand (NPS) and one receptor (NPSR) whose expression is relatively restricted. The therapeutic potential for the NPS-system resides in its unique behavioral profile, which is distinct from most systems. Central administration of NPS in mice enhances learning, increases arousal and produces anxiolytic-like effects. Discovery of small molecule NPSR agonists, let alone biased agonists has been extremely difficult. To our knowledge, no small molecule agonists have been disclosed in the patent or peer reviewed literature. Based on research conducted in our lab, we have identified the first and only biased, small molecule, NPS scaffold that retains full agonist properties in calcium mobilization assays, but has attenuated ability to increase cAMP levels. This is distinct from the native peptide (NPS) that displays roughly equal efficacy for both second messenger pathways. One of our biased agonists produces similar anxiolytic and memory enhancing effects as NPS in mice and can be blocked with RTI-118 a potent NPS antagonist. Based on this data we hypothesize biased agonists of the neuropeptide S receptor (NPSR) lacking cAMP activation will be useful for treating PTSD and other anxiety disorders where memory promotion is beneficial. The chemistry component of this application aims to improve NPSR potency, maintain signaling bias, and enhance drug-like properties of the lead compounds. The behavioral component of the application will focus on further establishing the behavioral profiles for our biased agonists. These aims will be accomplished through a collaboration of chemistry, in vitro pharmacology, and behavioral pharmacology programs.