Discovering Small Molecule Biased Agonists for the Neuropeptide S Receptor

发现神经肽 S 受体的小分子偏向激动剂

• 批准号: 9917358
• 负责人: Stewart Donaldson Clark
• 金额: $ 73.27万
• 依托单位: RESEARCH TRIANGLE INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-12 至 2022-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9917358
• 关键词: Acute; Affinity; Agonist; Amides; Amino Acids; Anti-Anxiety Agents; Anxiety; Anxiety Disorders; Arousal; Attenuated; Behavior; Behavioral; Benzodiazepines; Binding Proteins; Biological Assay; Biological Availability; Brain; Calcium; Calcium Signaling; Central Nervous System Diseases; Chemistry; Collaborations; Cyclic AMP; Data; Depression and Suicide; Disease; Drug Kinetics; Drug abuse; Event; G-Protein-Coupled Receptors; Generalized Anxiety Disorder; Goals; Hepatic; Human; Impairment; In Vitro; Lead; Learning; Legal patent; Ligands; Light; Link; Locomotion; Marble; Mediating; Memory; Memory Disorders; Metabolic; Modification; Motor Activity; Mus; Neuropeptide Receptor; Neuropeptides; Oral; Panic Disorder; Pathway interactions; Patients; Peer Review; Peptides; Permeability; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Pharmacotherapy; Phobias; Physiological; Plasma; Post-Traumatic Stress Disorders; Production; Property; Research; Resistance; Review Literature; Rodent; Second Messenger Systems; Series; Signal Pathway; Signal Transduction; Solubility; Stimulus; Substance abuse problem; Symptoms; System; Testing; Therapeutic; Work; absorption; analog; anxiety-like behavior; aqueous; base; behavioral pharmacology; blood-brain barrier penetration; common treatment; comorbid depression; conditioned fear; improved; in vitro Model; in vivo; meetings; novel; object recognition; programs; radioligand; receptor; release of sequestered calcium ion into cytoplasm; scaffold; small molecule; standard of care; tool; treatment of anxiety disorders

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.

与事件或事物相关的焦虑症（例如创伤后应激障碍 (PTSD)、恐惧症） 将受益于焦虑的同时缓解以及与该事件相关的记忆 诱发事件。尽管目前可用的抗焦虑药能够治疗急性焦虑，但它们已被证明 损害新记忆的形成。一些焦虑症的症状反应迅速且迅速 作用苯二氮卓类药物（例如恐慌症和广泛性焦虑症的初始和短期治疗 紊乱）。然而，其他疾病，例如创伤后应激障碍（PTSD），则具有持续性、高度侵入性的症状（闪回）， 对目前的治疗有抵抗力。此外，创伤后应激障碍 (PTSD) 与抑郁、自杀和药物有很高的合并症。 虐待本身就很难治疗，尤其是在患有使人衰弱的焦虑症的情况下。一个 选择性药物疗法既可以减少治疗过程中的焦虑，又可以增强记忆力 缺乏。神经肽S系统具有一种内源性配体（NPS）和一种受体（NPSR），其 表达相对受限。 NPS 系统的治疗潜力在于其独特的行为 profile，这与大多数系统不同。对小鼠进行 NPS 集中管理可增强学习能力， 增加兴奋度并产生抗焦虑样作用。小分子 NPSR 激动剂的发现，更不用说 有偏向的激动剂是极其困难的。据我们所知，目前还没有小分子激动剂 在专利或同行评审文献中公开。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保留钙完全激动剂特性的偏向小分子 NPS 支架 动员测定，但增加 cAMP 水平的能力减弱。这与天然肽不同 （NPS）对两种第二信使途径显示出大致相同的功效。我们的偏向激动剂之一 在小鼠中产生与 NPS 相似的抗焦虑和记忆增强作用，并且可以被 RTI-118 a 阻断 有效的 NPS 拮抗剂。根据这些数据，我们假设神经肽 S 受体的偏向激动剂 (NPSR) 缺乏 cAMP 激活将有助于治疗 PTSD 和其他影响记忆力的焦虑症 推广是有好处的。该应用的化学成分旨在提高 NPSR 效力，维持 信号偏向，并增强先导化合物的药物样特性。行为的组成部分 应用程序将侧重于进一步建立我们偏向激动剂的行为概况。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。