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

描述(申请人提供)：人们对复杂社会行为的生化基础了解甚少。由于这种知识差距，导致社会缺陷的疾病和症状不能得到有效治疗，建立有效治疗的合理方法受到限制。近年来，神经肽催产素在分娩和哺乳中的作用已经确立，并在一系列复杂的社会行为中得到了应用。几份报告的结果表明，催产素可以积极地影响焦虑、抑郁、精神病和成瘾。此外，催产素在形成社会依恋(母婴、一夫一妻制伴侣纽带)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障碍患者的深刻社会动机和认知缺陷。社会缺陷尤其使这些疾病的特征丧失能力，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的先导，用于以社会缺陷为特征的疾病状态。我们的目标是通过高通量筛选鉴定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的目标：1.通过高通量的筛选活动来鉴定人类OTR的选择性变构增强剂和激动剂。2.进行屏幕后二次分析，以验证我们的高通量屏幕中识别的命中。为了验证来自主屏幕的命中，将进行几个基于细胞的二次分析。我们为此开发了每一种化验方法。3.制定验证命中优化方案。我们将制定一项计划，优化通过我们的筛选工作确定的更有前途的活性物质类别。这些目标的完成将为科学界提供新的化学探针，以研究催产素在复杂哺乳动物社会行为中的作用。 与公共健康相关：催产素是一种影响哺乳动物复杂社会行为的多肽荷尔蒙。催产素途径的缺陷已经在包括精神分裂症和自闭症在内的几种人类疾病和障碍中实现，但仍然严重缺乏用于询问催产素途径和开发药物的化学探针。这项建议描述了一种高通量筛选，以确定催产素受体激动剂和阳性变构调节剂，作为设计化学探针的线索，以研究催产素途径，特别关注其在社会行为中的作用。

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.