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

JWS-USC-75-IX 的认知和抗精神病作用

• 批准号: 7531871
• 负责人: ALVIN V TERRY
• 金额: $ 19.13万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-08-01 至 2010-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7531871
• 关键词: Acetylcholine; Acetylcholinesterase Inhibitors; Address; Adverse effects; Affect; Affinity; Age; Aggressive behavior; Agitation; Alzheimer' s Disease; American; Amphetamines; Animal Behavior; Animal Model; Antipsychotic Agents; Apomorphine; Attention; Attenuated; Behavioral; Behavioral Symptoms; Cardiovascular system; Caregiver Burden; Caregivers; Caring; Class; Cognition Disorders; Cognitive; Cognitive deficits; Condition; Dementia; Developed Countries; Developing Countries; Development; Direct Costs; Dopamine Agonists; Drug Compounding; Drug Delivery Systems; Elderly; Emotional; Experimental Animal Model; Fright; Generations; Goals; Histamine H3 Receptors; Hyperglycemia; Hyperlipidemia; Impaired cognition; In Vitro; Individual; Institutionalization; Intention; Laboratories; Laboratory Research; Left; Link; Longevity; MK801; Macaca mulatta; Medicine; Memantine; Memory; Metabolic; Methods; Modeling; Molecular; Molecular Target; Monkeys; Motor Activity; Muscarinics; N-Methylaspartate; Neurobehavioral Manifestations; Neurodegenerative Disorders; Neurologic; Numbers; Patient Agents; Patients; Performance; Pharmaceutical Preparations; Population; Prevalence; Procedures; Process; Property; Psychotic Disorders; Public Health; Purpose; Ranitidine; Rattus; Reaction; Research; Risk; Risk Factors; Rodent; Sampling; Schizophrenia; Series; Short-Term Memory; Stroke; Testing; Therapeutic; Therapeutic Agents; Weight Gain; Work; age related cognitive disorder; aged; analog; base; concept; design; drug development; drug discovery; innovation; nonhuman primate; novel; nutrition; older patient; optimism; prepulse inhibition; programs; receptor; research study; single molecule; sound; therapeutic target; trend

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.

描述（由申请人提供）：发达国家老年人口迅速增加的一个不幸结果是与年龄相关的认知障碍（例如阿尔茨海默氏病（AD））的患病率不断增加。 AD 是一种毁灭性的神经退行性疾病，给患者和护理人员造成巨大的情感和经济损失。不幸的是，目前针对 AD 的可用疗法受到疗效有限、不良副作用以及该疾病的非常成问题的非认知行为症状（例如激越）未得到治疗的限制。此类行为症状是：临床上通常通过强效抗精神病药物进行治疗，这些药物已知会产生各种不良代谢和心血管反应，这对老年患者来说尤其成问题。因此，我们实验室的长期目标之一是为患有痴呆症行为和认知症状的患者开发更安全有效的治疗药物。我们在我们的药物发现计划中发现了一种特别有前途的化合物，它有潜力解决这些挑战。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）以及毒蕈碱 (M2) 乙酰胆碱和组胺的拮抗剂活性。 H3) 受体（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 是否是一种可行的原型 AD 治疗剂，并为具有多个治疗靶点的单分子实体的有效性提供概念证明。我们的中心假设是，由于其对多个药物靶点的活性，JWS-USC 75-IX 将在实验动物模型中表现出认知增强作用以及抗精神病活性。为了实现本申请的目标，我们提出了两个具体目标：1）确定 JWS-USC-75-IX 在老年非人类灵长类动物中的认知潜力； 2) 确定 JWS-USC-75-IX 在啮齿动物中的抗精神病潜力。为了实现这些目标，我们将在老年猴子的延迟样本匹配 (DMTS) 任务和干扰器版本 (DMTS-D) 中评估 JWS-USC-75-IX 分别对工作记忆和注意力的影响。我们将在安非他明诱导的运动活动模型和前脉冲抑制程序中确定该化合物对啮齿类动物的抗精神病潜力。该项目的重要性及其与公共卫生的相关性体现在这种新型化合物有可能解决两个主要的治疗挑战（即认知缺陷和非认知行为症状），这两个挑战不仅与 AD 等神经系统疾病相关，而且还涉及精神分裂症等精神疾病（即影响全世界数百万人的疾病）。公共卫生相关性认知缺陷和非认知行为症状是与阿尔茨海默病 (AD) 和精神分裂症等精神疾病相关的两个主要治疗挑战。我们合成了一种特别有前途的化合物（雷尼替丁类似物，JWS-USC-75-IX），它在体外对三个重要的分子靶标具有有效的促认知和抗精神病活性活性，因此有可能通过单分子解决这些治疗挑战。因此，本申请中提出的实验将确定（在动物行为模型中）JWS-USC-75-IX作为典型AD治疗剂的可行性，并将为具有多种治疗作用的单分子实体的有效性提供概念证明。目标。