DEVELOPMENT OF UNIFIED MODELS OF CCK RECEPTOR SUBTYPES

CCK受体亚型统一模型的开发

• 批准号: 3307663
• 负责人: Garland Ross Marshall
• 金额: $ 13.61万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-07-01 至 1995-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3307663
• 关键词: chemical models; cholecystokinin; conformation; cyclic peptides; inhibitor /antagonist; model design /development; neuropeptide receptor; peptide chemical synthesis; peptide hormone analog; receptor binding; stimulant /agonist

Cholecystokin (CCK), a 33-residue peptide, plays a major role in the gastrointestinal system (gall bladder contraction, amylase secretion, gut motility, food intake) as well as in the CNS as a neurotransmitter and/or neuromodulator. The CCK system, besides being of considerable therapeutic interest, offers a unique opportunity to decipher the structural basis of agonist action at its two receptor subtypes. This is due to the availability of a diverse set of peptide analogs, both agonist and antagonists, as well as non-peptide analogs, all antagonists. Models of the receptor-bound conformations of CCK at the two receptors provides a good interpretation of much of the current literature on peptide analogs. We propose to confirm and refine these models by synthesis of conformationally constrained analogs. The refined models will allow the alignment of the non-peptide antagonists and the :proposal of modifications which should convert them to agonists. This would demon- strate that the models are valid and that we understand the structural basis of the differences between agonists and antagonists. The ultimate goal of this proposal is a predictive, quantitative model for the two CCK receptor subtypes which will allow the design and synthesis of novel therapeutic agents.

胆囊收缩素（CCK）是一种33个残基的肽，在胆囊收缩中起主要作用。 胃肠道系统（胆囊收缩、淀粉酶分泌、肠 运动，食物摄入）以及在CNS中作为神经递质和/或 神经调质 CCK系统除了具有相当大的 治疗的兴趣，提供了一个独特的机会来破译 在其两种受体亚型上的激动剂作用的结构基础。 这是 由于可获得多种肽类似物， 和拮抗剂，以及非肽类似物，所有拮抗剂。 模型 CCK在两种受体上的受体结合构象的变化提供了 一个很好的解释，目前的许多文献肽 类似物 我们建议通过综合以下因素来确认和完善这些模型： 构象受限的类似物。 改进后的模型将允许 非肽拮抗剂的排列和： 这些修饰应该将它们转化为激动剂。 这将恶魔- 证明模型是有效的，我们理解结构 激动剂和拮抗剂之间的差异。 最终 本建议的目标是一个预测，定量模型的两个CCK 受体亚型，这将允许设计和合成新的 治疗剂。