Novel serotonergic, pro-cognitive antipsychotic therapies

新型血清素能、促认知抗精神病药物疗法

• 批准号: 8057518
• 负责人: Silvana Leit
• 金额: $ 34.98万
• 依托单位: GALENEA CORPORATION
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8057518
• 关键词: 5-HT6 receptor; Achievement; Address; Adverse effects; Affect; Affinity; Agonist; Animal Model; Antipsychotic Agents; Apomorphine; Area; Attention; Brain Diseases; Brain region; Categories; Characteristics; Chemicals; Chronic; Clinical; Cognition; Cognitive; Cognitive deficits; Delusions; Desire for food; Development; Diabetes Mellitus; Disease; Dopamine D2 Receptor; Drug Industry; Drug Kinetics; Emotional; Family Caregiver; Family member; Glutamates; Goals; HTR2A gene; Hallucinations; Human; Impairment; In Vitro; Indoles; Lead; Learning; Medical; Medicine; Memory; Mental disorders; Motor; Neurobehavioral Manifestations; Outcome; Outcomes Research; Pathway interactions; Patients; Performance; Performance at work; Pharmaceutical Preparations; Phase; Physiologic pulse; Population; Positioning Attribute; Pre-Clinical Model; Process; Property; Psychotic Disorders; Rattus; Refractory; Regulation; Research; Risk; Schizophrenia; Series; Serotonin Receptor 5-HT2C; Short-Term Memory; Signal Transduction; Small Business Innovation Research Grant; Social isolation; Societies; Solid; Staging; Symptoms; Testing; Therapeutic; Weight Gain; atypical antipsychotic; base; cholinergic; classical conditioning; design; drug candidate; effective therapy; efficacy evaluation; improved; in vivo; lead series; meetings; neurotransmission; novel; novel strategies; novel therapeutic intervention; object recognition; prevent; programs; response; scaffold; serotonin receptor; stereotypy; therapeutic target

DESCRIPTION (provided by applicant): This application, "Novel serotonergic, pro-cognitive antipsychotic therapies", is in response to PA-08-142: "Pharmacologic Agents and Drugs for Mental Disorders" (SBIR [R43/R44]). Schizophrenia is a devastating brain disorder that affects approximately 0.7% of the global population. The symptoms of schizophrenia can be grouped into three major categories: positive (e.g. hallucinations and delusions), negative (e.g. social isolation and inappropriate emotional response), and cognitive symptoms. The cognitive symptoms of schizophrenia include impaired attention and disruption of working memory, an essential type of short term memory. These fundamental cognitive processes are critical for the performance of day-to-day activities, and their disruption in schizophrenia is a key factor underlying the inability of patients to integrate successfully into society. Indeed, the cognitive deficits associated with schizophrenia are recognized as a core component of the disorder. Currently available antipsychotic therapies are effective at ameliorating the positive symptoms of schizophrenia, but they are not effective at treating the negative or cognitive symptoms of the disease. Moreover, these therapies often cause significant side effects such as motor disturbances, weight gain, and diabetes. For these reasons, schizophrenia represents a major area of unmet medical need which must be addressed by the discovery and development of new antipsychotic therapies that are effective at treating the cognitive symptoms of schizophrenia with reduced potential for side effects. The overall goal of this proposal is to optimize a series of lead compounds we have identified with dual 5-HT2C receptor agonist and 5-HT6 receptor antagonist activities. Compounds with this novel pharmacological profile hold promise for yielding safe and effective treatments for the positive as well as the cognitive symptoms of schizophrenia. Such compounds are likely to have a significantly reduced risk for generating the undesirable side effects that are typically observed with currently available antipsychotic therapies. Successful completion of the specific aims outlined in this proposal will result in the identification of lead compounds with desirable pharmacological and drug-like properties. Furthermore, proof-of-concept for this novel target profile will be achieved by demonstrating antipsychotic and pro-cognitive efficacy in animal models with a selected lead compound. These achievements will provide a solid basis for a Phase II SBIR application to support further research aimed at selecting a clinical development candidate for the treatment of schizophrenia and its cognitive symptoms. A clinical development candidate with this novel profile would comprise a valuable asset within the pharmaceutical industry and would provide the basis of a successful commercial outcome for the research program. The research outlined in this proposal will directly benefit patients and their families and caregivers by leading to the discovery of safer and more effective medicines for the treatment of schizophrenia. PUBLIC HEALTH RELEVANCE: We have discovered a series of compounds with a unique target profile for specific serotonin receptors that are relevant to schizophrenia and cognition. Based on this discovery, we are optimizing these compounds to identify a new class of candidate drugs for treatment of schizophrenia and its severe cognitive deficits. Our goal is to discover new therapies that are more effective than current treatments with reduced potential for side effects. This research will thus have a positive impact on the significant population of schizophrenia patients and their family members and caregivers, which includes many millions of people worldwide. In particular, improving the cognitive outcome in schizophrenia will help patients to improve their job performance and to integrate into society more effectively.

描述（由申请人提供）：本申请“新型血清素能促认知抗精神病疗法”是对 PA-08-142 的回应：“治疗精神障碍的药理学制剂和药物”(SBIR [R43/R44])。精神分裂症是一种毁灭性的脑部疾病，影响着全球约 0.7% 的人口。精神分裂症的症状可分为三大类：阳性症状（例如幻觉和妄想）、阴性症状（例如社交孤立和不适当的情绪反应）和认知症状。精神分裂症的认知症状包括注意力受损和工作记忆破坏（短期记忆的一种重要类型）。这些基本的认知过程对于日常活动的表现至关重要，它们对精神分裂症的破坏是患者无法成功融入社会的关键因素。事实上，与精神分裂症相关的认知缺陷被认为是该疾病的核心组成部分。目前可用的抗精神病药物可有效改善精神分裂症的阳性症状，但不能有效治疗该疾病的阴性或认知症状。此外，这些疗法通常会引起明显的副作用，例如运动障碍、体重增加和糖尿病。由于这些原因，精神分裂症是未满足的医疗需求的一个主要领域，必须通过发现和开发新的抗精神病疗法来解决，这些疗法可有效治疗精神分裂症的认知症状，并减少副作用的可能性。该提案的总体目标是优化我们已确定的具有双重 5-HT2C 受体激动剂和 5-HT6 受体拮抗剂活性的一系列先导化合物。具有这种新颖药理学特征的化合物有望为精神分裂症的阳性症状和认知症状提供安全有效的治疗方法。此类化合物可能显着降低产生不良副作用的风险，而目前可用的抗精神病疗法通常会观察到这种副作用。成功完成该提案中概述的具体目标将导致鉴定出具有理想药理学和药物样特性的先导化合物。此外，通过在动物模型中使用选定的先导化合物证明抗精神病和促认知功效，将实现这一新靶点的概念验证。这些成就将为 II 期 SBIR 申请提供坚实的基础，以支持旨在选择治疗精神分裂症及其认知症状的临床开发候选药物的进一步研究。具有这种新颖特征的临床开发候选药物将成为制药行业的宝贵资产，并将为研究项目取得成功的商业成果奠定基础。该提案中概述的研究将发现更安全、更有效的治疗精神分裂症的药物，从而直接造福患者及其家人和护理人员。 公共健康相关性：我们发现了一系列对与精神分裂症和认知相关的特定血清素受体具有独特靶标特征的化合物。基于这一发现，我们正在优化这些化合物，以确定一类用于治疗精神分裂症及其严重认知缺陷的新型候选药物。我们的目标是发现比现有疗法更有效且副作用可能性更低的新疗法。因此，这项研究将对大量精神分裂症患者及其家人和护理人员产生积极影响，其中包括全世界数百万人。特别是，改善精神分裂症的认知结果将有助于患者提高工作绩效并更有效地融入社会。