Novel treatment of posttraumatic stress disorder

描述(由申请人提供)：本申请“创伤后应激障碍的新疗法”解决了有效治疗创伤后应激障碍(PTSD)的迫切需要。由创伤经历激活的关键神经信号级联反应是由兴奋性神经递质谷氨酸启动的。NMDA受体是谷氨酸受体的一个亚型，激活后会导致神经元型一氧化氮合酶(NNOS)的激活，最终导致信号分子一氧化氮(NO)的产生增加。这些事件触发异常的突触可塑性，这与 创伤后应激障碍的启动和维持。突触后密度蛋白95(PSD95)针对nNOS的NMDA受体，因此是激活nNOS的NMDA受体所必需的。该项目的首席研究员赖博士首次表明，小分子抑制剂IC87201在体外扰乱了nNOS和PSD95之间的功能性蛋白质-蛋白质相互作用，并在体内减轻了NMDA受体依赖的痛觉过敏。我们的临床前团队由Shekhar博士(Anagin的创始人)领导，现在已经证明IC87201和相关的类似物ZL006可以阻止条件性恐惧的长期编码，即使在恐惧条件反射过程发生后(即创伤后)。与NMDA受体拮抗剂不同，这些蛋白质相互作用抑制剂是有效的，不会损害运动或记忆。因此，信号分区的中断代表了一种创新的方法，以开发副作用更少的焦虑症的新治疗方法。我们组建了一个具有协同和互补专业知识的协作团队，将药物发现(LAI)、开发新的临床前应激和记忆模型(Shekhar和Hohmann)、先导化合物的化学优化(Thakur)和靶标验证(Lai和Hohmann)方面的广泛经验结合在一起，以开展在两个特定目标下提出的工作。该提案的目标1将描述我们的先导抑制剂的药代动力学特征和口服疗效。然后，AIM 2将使用传统的药物药物化学方法来设计和开发与母体化合物相比具有更好的溶解性和效力的后备化学系列。这项SBIR第一阶段研究的结果将为进一步的先导优化和临床前开发nNOS靶向抑制剂作为第二阶段治疗创伤后应激障碍的新疗法奠定基础。这些研究有望验证信号蛋白区隔的破坏作为一种创新和可行的药物开发方法。具有新的化学结构的有效药物疗法的开发具有有限的副作用，预计将降低不断上升的医疗成本，并减轻创伤后应激障碍患者不必要的痛苦。

DESCRIPTION (provided by applicant): The present application "Novel Treatment for Posttraumatic Stress Disorder" addresses the critical need for efficacious treatments for posttraumatic stress disorder (PTSD). A key neural signaling cascade activated by a trauma experience is initiated by the excitatory neurotransmitter glutamate. Activation of the NMDA receptor, a glutamate receptor subtype, results in subsequent activation of the enzyme neuronal nitric oxide synthase (nNOS) and, ultimately, an 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 and is, therefore, required for NMDA receptor activation of nNOS. Dr. Lai, Principal investigator for this project, first showed that the small molecule inhibitor IC87201 disrupts the functional protein-protein interaction between nNOS and PSD95 in vitro and attenuates NMDA receptor dependent hyperalgesia in vivo. Our preclinical team, led by Dr. Shekhar (Founder of Anagin), has now shown 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 without impairing motor movement or memory. Thus, disruption of signal compartmentalization represents an innovative approach to develop novel treatments for anxiety disorders with fewer side-effects. We have assembled a collaborative team with synergistic and complementary expertise to unite extensive combined experience in drug discovery (Lai), development of novel preclinical stress and memory models (Shekhar and Hohmann), chemical optimization of lead compounds (Thakur) and target validation (Lai and Hohmann) to conduct work proposed under two Specific Aims. Aim 1 of this proposal will characterize the pharmacokinetic profile and oral efficacy of our lead inhibitors. Aim 2 will then use a traditional drug medicinal chemistry approach to design and develop a back up chemical series with improved solubility and potency compared to the parent compounds. Results from this SBIR Phase I study will lay the foundation for further lead optimization and preclinical development of nNOS targeting inhibitors as novel treatments for PTSD in Phase II. These studies are expected to validate the disruption of signal protein compartmentalization as an innovative and feasible approach to drug development. 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.