Novel treatment of posttraumatic stress disorder

项目摘要 本申请《创伤后应激障碍的新疗法》解决了 对创伤后应激障碍(PTSD)的更有效的治疗。兴奋性神经递质， 谷氨酸，在创伤经历中激活一个关键的神经信号级联反应。在这种激活过程中，谷氨酸 结合并激活谷氨酸受体亚型NMDA受体。绑定和激活会触发 在受体处形成复合体，并导致神经元型一氧化氮合酶的激活 (NNOS)和伴随而来的信号分子一氧化氮(NO)的产生增加。这些事件 触发异常突触可塑性，与创伤后应激障碍的启动和维持有关。突触后 密度蛋白95(PSD95)将nNOS靶向NMDA受体，促进该信号的形成 很复杂。因此，NMDA受体激活nNOS需要PSD95。赖，Anagin联合创始人和 该项目的首席研究员首先表明，小分子IC87201破坏了功能 NNOS与PSD95体外蛋白质相互作用及对NMDA受体依赖的抑制作用 活体痛觉过敏。Anagin是一家总部位于印第安纳州的小企业，它在印第安纳大学的临床前团队， 由Shekhar博士(Anagin的联合创始人)领导的，已经证明IC87201和相关的类似物ZL006，阻断 对条件性恐惧的长期编码，即使在恐惧条件化过程已经发生之后(即，后 创伤)。与Nmda受体拮抗剂不同，这些蛋白质相互作用抑制剂在抑制 在建立良好的临床前模型中出现类似创伤后应激障碍的症状，而不会产生运动或记忆障碍。 因此，信号分区的中断代表了开发新的治疗方法的创新方法 用于副作用较少的焦虑症。在Anagin成功的SBIR第一阶段研究中，该团队 建立了其第一代先导化合物的结构-活性-关系和口服疗效 并确定了一种很有前途的新化学系列。此第二阶段SBIR的目标是提供可口服的 候选药物和启动支持IND的研究通过两个具体目标来描述。目标1：执行销售线索 选择药物开发候选者的优化研究。目标2：验证药物开发 IND-Enabling研究的候选人。将使用传统的药物药物化学方法来设计和 开发新的类似物，与母体相比具有更好的药代动力学特性和效力 化合物。Anagin预计在赠款期间结束时完成初步的支持IND的研究。这个 开发副作用有限的新型化学结构的有效药物治疗 Profile有望降低不断攀升的医疗成本，并减轻创伤后应激障碍的不必要痛苦 病人。最终目标是FDA IND提交PTSD或PTSD第一阶段临床试验候选药物 焦虑症。

Project Summary The present application “Novel Treatment for Posttraumatic Stress Disorder” addresses the critical need for more efficacious treatments for posttraumatic stress disorder (PTSD). The excitatory neurotransmitter, glutamate, activates a key neural signaling cascade upon a trauma experience. In this activation, glutamate binds to and activates the NMDA receptor, a glutamate receptor subtype. Binding and activation triggers the formation of a complex at the receptor and leads to activation of the enzyme neuronal nitric oxide synthase (nNOS) and a concomitant increase in the production of the signaling molecule nitric oxide (NO). These events trigger aberrant synaptic plasticity that is implicated in the initiation and maintenance of PTSD. Postsynaptic density protein 95 (PSD95) targets nNOS to the NMDA receptor facilitating the formation of this signaling complex. PSD95 is therefore, required for NMDA receptor activation of nNOS. Lai, Anagin co-founder and principal investigator for this project, first showed that the small molecule, IC87201, disrupts the functional protein-protein interaction between nNOS and PSD95 in vitro and attenuates NMDA receptor dependent hyperalgesia in vivo. Anagin, an Indiana-based small business and its preclinical team at Indiana University, led by Dr. Shekhar (co-founder of Anagin), has demonstrated that IC87201 and a related analog, ZL006, block the long-term encoding of conditioned fear even after a fear conditioning session has occurred (i.e. post- trauma). Unlike NMDA receptor antagonists, these protein interaction inhibitors are efficacious in suppressing PTSD-like symptoms in a well-established preclinical model without producing motor or memory impairment. Thus, disruption of signal compartmentalization represents an innovative approach to develop novel treatments for anxiety disorders with fewer side-effects. In Anagin's successful SBIR Phase I studies, the team established positive structural-activity-relationship and demonstrated oral efficacy of its first-generation lead and identified a promising new chemical series. The goal of this Phase II SBIR is to deliver an orally available drug candidate and initiate IND-enabling studies delineated through two specific aims. Aim 1: Perform lead optimization studies to select a Drug Development Candidate. Aim 2: Validate the Drug Development Candidate in IND-enabling studies. A traditional drug medicinal chemistry approach will be used to design and develop novel analogs with improved pharmacokinetic properties and potency compared to the parent compounds. Anagin anticipates completion of initial IND-enabling studies at the end of the grant period. The development of effective pharmacotherapies with novel chemical structures that possess limited side-effect profiles is expected to drive down escalating health care costs and alleviate unnecessary suffering in PTSD patients. The ultimate goal is an FDA IND submission of a drug candidate for Phase I clinical trials in PTSD or anxiety disorders.