Procognitive and Antipsychotic Actions of JWS-USC-75-IX

描述(申请人提供)：发达国家老年人口迅速增长的一个不幸结果是与年龄相关的认知障碍的日益流行，如阿尔茨海默病(AD)。AD是一种毁灭性的神经退行性疾病，对患者和照顾者造成巨大的情感和经济损失。不幸的是，目前可用的治疗AD的方法受到以下因素的限制：疗效不佳，副作用较大，以及非常有问题的非认知行为症状(如激越)得不到治疗的事实。因此，这种行为症状通常通过有效的抗精神病药物在临床上得到控制，这些药物是已知会产生各种不良代谢和心血管反应的化合物，这些反应在老年患者中尤其严重。因此，我们实验室的一个长期目标是为患有痴呆的行为和认知症状的患者开发更安全和有效的治疗药物。我们已经在我们的药物发现计划中确定了一种特别有希望的化合物，它具有应对这些挑战的潜力。该化合物JWS-USC-75-IX是一种雷尼替丁类似物，具有有效的乙酰胆碱酯酶抑制剂(AChEI)特性(即，增强记忆的重要治疗靶点)以及M(M2)乙酰胆碱和组胺(H3)受体的拮抗活性(即，认知增强和抗精神病活性的重要药物靶点)。因此，本申请的目的是在动物模型中确定JWS-USC-75-IX是否是一种可行的典型AD治疗剂，并为具有多个治疗靶点的单分子实体的有用性提供概念证明。我们的中心假设是，由于其在多个药物靶点的活性，JWS-USC 75-IX将在实验动物模型中显示出认知增强作用和抗精神病活性。为了实现这一应用的目标，我们提出了两个具体的目标：1)确定JWS-USC-75-IX在老年非人灵长类动物中的先兆认知潜力；2)确定JWS-USC-75-IX在啮齿类动物中的抗精神病潜力。为了解决这些目标，我们将在延迟匹配样本(DMTS)任务和该方法的分心版本(DMTS-D)中分别评估JWS-USC-75-IX对老年猴子工作记忆和注意力的影响。我们将在苯丙胺诱导的运动活动模型和脉冲前抑制程序中确定该化合物在啮齿动物中的抗精神病潜力。该项目的重要性及其与公共健康的相关性通过这种新型化合物解决两大治疗挑战(即认知缺陷和非认知行为症状)的潜力得到了例证，这两个挑战不仅与阿尔茨海默病等神经疾病有关，而且与精神分裂症等精神疾病(即影响全球数百万人的疾病)有关。公共卫生相关性认知缺陷和非认知行为症状是阿尔茨海默病(AD)和精神分裂症等精神疾病相关的两大治疗挑战。我们已经合成了一种特别有希望的化合物(雷尼替丁类似物，JWS-USC-75-IX)，它在体外对三个重要的分子靶点具有潜在的认知和抗精神病活性，从而可能在单个分子中解决这些治疗挑战。因此，本申请中提出的实验将(在动物行为模型中)确定JWS-USC-75-IX作为典型AD治疗剂的可行性，并将为具有多个治疗靶点的单分子实体的有用性提供概念证明。

DESCRIPTION (provided by applicant): An unfortunate result of the rapid rise in the geriatric population in developed countries is the increasing prevalence of age-related cognitive disorders such as Alzheimer's disease (AD). AD is a devastating neurodegenerative illness that inflicts an enormous emotional and financial toll on patients as well as caregivers. Unfortunately, the currently available therapies for AD are limited by modest efficacy, adverse side effects, and the fact that the very problematic non-cognitive behavioral symptoms (e.g., agitation) of the illness are left untreated. Such behavioral symptoms are thus; often managed clinically by potent antipsychotic drugs, compounds that are known to produce a variety of adverse metabolic and cardiovascular reactions which are particularly problematic in older patients. Accordingly, one long-term goal of our laboratory is to develop more safe and effective therapeutic agents for patients suffering from both the behavioral and cognitive symptoms of dementia. We have identified one especially promising compound in our drug discovery program that has potential to address these challenges. The compound, JWS-USC-75-IX, is a ranitidine analog that has potent acetylcholinesterase inhibitor (AChEI) properties (i.e., an important therapeutic target for memory enhancement) as well as antagonist activity at both muscarinic (M2) acetylcholine and histamine (H3) receptors (i.e., important drug targets for both cognitive enhancement and antipsychotic activity). Thus, the objective of this application is to determine in animal models if JWS-USC-75-IX is a viable prototypical AD therapeutic agent as well as to provide a proof of concept for the usefulness of single molecular entities with multiple therapeutic targets. Our central hypothesis is that as a result of its activity at multiple drug targets, JWS-USC 75-IX will demonstrate cognitive enhancing effects as well as antipsychotic activity in experimental animal models. To achieve the objectives of this application, we propose two specific aims: 1) To determine the procognitive potential of JWS-USC-75-IX in the aged non-human primate; and 2) To determine the antipsychotic potential of JWS-USC-75-IX in rodents. To address these aims, we will evaluate JWS-USC-75-IX in a delayed match to sample (DMTS) task and a distractor version of this method (DMTS-D) in aged monkeys for effects on working memory and attention, respectively. We will determine antipsychotic potential of the compound in rodents in an amphetamine-induced locomotor activity model and a prepulse inhibition procedure. The significance of this project and its relevance to public health is exemplified by the potential of this novel compound to address two major therapeutic challenges (i.e., cognitive deficits and non-cognitive behavioral symptoms) that are associated not only with neurological illnesses such as AD, but also in psychiatric illnesses such as schizophrenia (i.e., conditions that affect millions of people worldwide). PUBLIC HEALTH RELEVANCE Cognitive deficits and non-cognitive behavioral symptoms are two major therapeutic challenges associated with Alzheimer's disease (AD) and psychiatric illnesses such as schizophrenia. We have synthesized a particularly promising compound (the ranitidine analog, JWS-USC-75-IX) that has potent activity in vitro at three important molecular targets for procognitive and antipsychotic activity, thus potentially addressing these therapeutic challenges in a single molecule. The experiments proposed in this application will thus determine (in animal behavior models) the viability of JWS-USC-75-IX as a prototypical AD-therapeutic agent, and will provide a proof of concept for the usefulness of single molecular entities with multiple therapeutic targets.