Allosteric Potentiators of the Oxytocin System for the Control of Social Motivati

控制社会动机的催产素系统的变构增效剂

• 批准号: 7694094
• 负责人: MICHAEL B JARSTFER
• 金额: $ 2.5万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-16 至 2010-04-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7694094
• 关键词: Affect; Agonist; Anxiety; Attention; Autistic Disorder; Biochemical; Biological Assay; Biology; Birth; Brain; Cell Line; Cells; Chemicals; Clinical; Cognition; Collaborations; Communities; Complex; Development; Disease; Diversity Library; Ensure; FDA approved; Female; G-Protein-Coupled Receptors; Goals; Human; Infant; Intervention; Lactation; Letters; Libraries; Mammals; Measures; Memory; Molecular Bank; Mothers; Motivation; Neuropeptides; Oxytocin; Oxytocin Receptor; Pair Bond; Pathway interactions; Patients; Personality Disorders; Pharmaceutical Preparations; Pharmacologic Substance; Pharmacological Treatment; Phase; Production; Psychotherapy; Psychotic Disorders; Receptor Activation; Recovery; Reporting; Research Project Grants; Role; Schizophrenia; Screening procedure; Sexual Arousal; Sexual Arousal Disorder; Social Behavior; Social Controls; Specificity; Syndrome; System; Therapeutic; V1 Receptors; Validation; Vasopressin Receptor; addiction; autism spectrum disorder; base; depression; design; drug discovery; effective therapy; high throughput screening; human disease; knowledge of results; male; neurochemistry; peptide hormone; public health relevance; small molecule libraries; social; social attachment

DESCRIPTION (provided by applicant): The biochemical underpinnings of complex social behavior are poorly understood. As a result of this knowledge gap, diseases and syndromes that result in social deficits cannot be effectively treated and rational approaches toward establishing effective treatment are restricted. Recently, the neuropetide oxytocin, which has well established roles in parturition and lactation, has been implemented in a wide range of complex social behaviors. Results from several reports suggest that oxytocin can positively affect anxiety, depression, psychosis and addiction. Additionally, the potency of oxytocin in forming social attachments (mother-infant, monogamous pair bonds) and social memories suggests that increased oxytocin activity in the brain can ameliorate the profound social motivation and cognition deficits of patients with autism spectrum disorders, schizophrenia or severe personality disorders. Social deficits are particularly disabling features of these disorders for which we have no effective pharmacological treatments. The hypothesis of this research project is that oxytocin receptor agonist and positive allosteric modulators would serve as leads for pharmaceutical intervention in disease states characterized by social deficits. Our objective is to identify agonists and positive allosteric modulators through a high throughput screen. To achieve our object we propose three specific aims: 1. Identify selective allosteric potentiators and agonists of the human OTR through a high throughput screening campaign. 2. Conduct post screen secondary analysis to validate hits identified in our high throughput screen. In order to validate hits from the primary screen, several cell-based secondary assays will be conducted. We have developed each assay for this purpose. 3. Develop a plan for optimization of validated hits. We will develop a plan to optimize the more promising class of actives identified through our screening efforts. The completion of these aims will provide the scientific community with new chemical probes to study the roles of oxytocin in complex mammalian social behavior. PUBLIC HEALTH RELEVANCE: Oxytocin is a peptide hormone that affects complex social behaviors in mammals. Deficits in the oxytocin pathway have been implemented in several human diseases and disorders, including schizophrenia and Autism, but there remains a severe dearth of chemical probes to interrogate the oxytocin pathway and to develop pharmaceutical agents. This proposal describes a high throughput screen to identify oxytocin receptor agonists and positive allosteric modulators to be used as leads for the design of chemical probes to investigate the oxytocin pathway with particular attention to its role in social behavior.

描述（由申请人提供）：人们对复杂社会行为的生化基础知之甚少。由于这种知识差距，导致社会缺陷的疾病和综合症无法得到有效治疗，并且建立有效治疗的合理方法受到限制。最近，神经肽催产素在分娩和哺乳中发挥了明确的作用，已广泛应用于各种复杂的社会行为中。几份报告的结果表明，催产素可以对焦虑、抑郁、精神病和成瘾产生积极影响。此外，催产素在形成社会依恋（母婴、一夫一妻制的伴侣关系）和社会记忆方面的效力表明，大脑中催产素活性的增加可以改善自闭症谱系障碍、精神分裂症或严重人格患者的深刻的社会动机和认知缺陷失调。社交缺陷是这些疾病的特别致残的特征，我们没有有效的药物治疗方法。该研究项目的假设是，催产素受体激动剂和正变构调节剂将作为药物干预以社会缺陷为特征的疾病状态的先导。我们的目标是通过高通量筛选来识别激动剂和正变构调节剂。为了实现我们的目标，我们提出了三个具体目标： 1. 通过高通量筛选活动鉴定人类 OTR 的选择性变构增强剂和激动剂。 2. 进行筛选后二次分析以验证在我们的高通量筛选中识别的命中。为了验证初级筛选的结果，将进行几种基于细胞的二级测定。我们为此目的开发了每种检测方法。 3. 制定优化已验证点击的计划。我们将制定一项计划，优化通过筛选工作确定的更有前景的活性物质类别。这些目标的完成将为科学界提供新的化学探针来研究催产素在复杂的哺乳动物社会行为中的作用。 公共卫生相关性：催产素是一种影响哺乳动物复杂社会行为的肽激素。催产素途径的缺陷已在多种人类疾病和病症中出现，包括精神分裂症和自闭症，但仍然严重缺乏用于研究催产素途径和开发药剂的化学探针。该提案描述了一种高通量筛选，用于鉴定催产素受体激动剂和正变构调节剂，作为设计化学探针的先导，以研究催产素途径，特别关注其在社会行为中的作用。