DEVELOPMENT OF UNIFIED MODELS OF CCK RECEPTOR SUBTYPES

胆囊素(CCK)是一种由33个氨基酸残基组成的多肽，在胆囊炎的发生、发展中起重要作用。 胃肠系统(胆囊收缩、淀粉酶分泌、肠道 运动性、食物摄入量)以及在中枢神经系统作为神经递质和/或 神经调节剂。CCK系统，除了有相当大的 治疗兴趣，提供了一个独特的机会来破译 其两个受体亚型的激动剂作用的结构基础。这是 由于有一套不同的多肽类似物，这两种激动剂 和拮抗剂，以及非肽类似物，都是拮抗剂。模型 两个受体上CCK的受体结合构象提供了 对当前许多关于肽的文献的很好的解释 类比。我们建议通过合成以下各项来确认和完善这些模型 构象受限的类似物。精致的模型将允许 非肽类拮抗剂的比对及建议 可以将它们转化为激动剂的修饰。这会让人心烦- 确保模型是有效的，并且我们理解结构 激动剂和拮抗剂之间的区别。终极的 这项建议的目标是为两个CCK建立一个预测性的量化模型 受体亚型将允许设计和合成新的 治疗剂。

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.