权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

SP RECEPTOR BINDING SITES FOR AGONISTS AND ANTAGONISTS

激动剂和拮抗剂的 SP 受体结合位点

基本信息

批准号：
2839354
负责人：
NORMAN D BOYD
金额：
$ 28.13万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
1992
资助国家：
美国
起止时间：
1992-12-01 至 2001-06-30
项目状态：
已结题

项目摘要

This renewal is a continuation of studies on the structure and function of the substance P (SP) receptor. The long term objective of this proposal is to understand, at the molecular level, the basis of agonist and antagonist specificity, receptor activation and downstream signaling events. Our approach will be to use photoreactive SP analogs containing p-benzoylphenylalanine substituted at different positions in the eleven amino acid sequence of SP. The site(s) of covalent attachment of these photoligands on the SP receptor will be determined by MALDI-mass spectrometric analysis of isolated photolabeled receptor fragments, which are generated by enzymatic and/or chemical cleavage of the receptor. These studies will aid in defining the SP binding pocket and orient the peptide within that pocket. We will develop benzophenone-containing derivatives of non-peptide SP antagonists as photoprobes of the antagonist binding domain(s). An understanding of the relationship between the binding sites for peptide agonist and the non-peptide antagonists forms the foundation for understanding underlying mechanisms of antagonism, which is essential for drug development. The availability of photoreactive peptide agonists, together with chemical crosslinking and immunodetection, provides us with tools to identify specific G proteins and other regulatory proteins which interact with the SP receptor. This approach will provide important information about the signal transduction machinery associated with the SP receptor. As it has been estimated that up to 60 percent of all medicines used today exert their effects through G protein signaling pathways, these studies may provide new and interesting information of basic clinical relevance. The peptide substance P has attracted considerable attention because of its multiple biological activities: as a neurotransmitter in the central, sensory and autonomic nervous systems; as an agent that causes contraction of smooth muscle in the gastrointestinal tract and as a mediator of inflammation and immune responses. SP has been implicated in a number of sensory and neurogenerative disorders. The information provided by our continuing effort should form the basis for understanding and development of novel SP receptor agonists and antagonists.

这一更新是对结构和功能研究的继续 P物质(SP)受体。这样做的长期目标是建议在分子水平上理解激动剂的基础拮抗剂特异性、受体激活和下游信号转导事件。我们的方法将是使用光反应SP类似物含有不同位置取代的对苯甲酰苯丙氨酸 SP的11个氨基酸序列。共价键的位置(S) 这些光配体在SP受体上的附着将被确定离体光标记化合物的MALDI-MS分析受体片段，由酶和/或化学物质产生受体的裂解。这些研究将有助于定义SP 结合口袋，并在口袋中定位多肽。我们会非肽SP含二苯甲酮衍生物的开发拮抗剂作为拮抗剂结合域的光探针(S)。一个对多肽结合部位之间关系的认识激动剂和非肽拮抗剂构成了了解对抗的潜在机制，这是至关重要的用于药物开发。光反应肽的可利用性激动剂，再加上化学交联和免疫检测，为我们提供工具来识别特定的G蛋白和其他与SP受体相互作用的调节蛋白。这种方法将提供有关信号转导的重要信息与SP受体相关的机械。正如所估计的那样今天使用的所有药物中高达60%发挥了作用通过G蛋白信号通路，这些研究可能提供新的和基本临床相关的有趣信息。 P物质已经引起了相当大的关注，因为它的多种生物学活动：作为中枢的神经递质，感觉和自主神经系统；作为一种能引起胃肠道和胃肠道的平滑肌收缩炎症和免疫反应的中介物。SP已被牵涉到许多感官和神经生成障碍。这个我们的持续努力提供的信息应成为新型SP受体激动剂的认识和开发对抗者。