RECEPTOR SPECIFIC ENKEPHALIN ANALOGUES

我们建议开发一系列的环状和其他构象 限制性肽类似物具有高受体选择性、高 激动剂或拮抗剂效力，体内高稳定性， δ和μ阿片受体的活性。 为此，我们的计划 利用多学科方法结合现代合成氨基酸 肽化学、构象分析、动力学和肽药物 设计，与生物化学，生物物理，生理，和行为 药理学 我们的具体目标包括：1）设计，合成， 用δ阿片受体激动剂评价新的脑啡肽类似物 活性和选择性; 2）δ阿片受体的发育 高选择性拮抗剂的设计、合成与评价 环，构象约束生长抑素样肽， 或无生长抑素活性，但对μ 阿片受体; 4）详细检查构象和 从1，2， 和3获得洞察到更有选择性的合理设计或 使用现代图形和计算方法的有效类似物; 5） 详细检查这些化合物在μ和δ上的结合活性 阿片受体（最具选择性的类似物，可被放射性标记， 通过现代放射自显影方法定位于脑中的受体）; 6） 获得阿片类激动剂和拮抗剂的综合评价， 体外和体内活性的类似物，我们已经制备和比较 这些活动与标准药物;和7）使用上述结果， 为δ和μ设计更特异、更有效的类似物 受体的 这项研究的长期目标是开发一种 了解各种阿片受体的生理作用， 并开发这些受体的配体， 疾病的治疗。

We propose to develop a series of cyclic and otherwise conformationally restricted peptide analogues which have high receptor selectivity, high agonist or antagonist potency, high stability in vivo, and prolonged activity for delta and mu opioid receptors. For this purpose, our program utilizes a multidisciplinary approach combining modern synthetic amino acid and peptide chemistry, conformational analysis, dynamics, and peptide drug design, with biochemical, biophysical, physiological, and behavior pharmacology. Our specific aims include: 1) design, synthesis and evaluation of novel enkephalin analogues with delta opioid receptor agonist activity and selectivity; 2) development of delta opioid receptor antagonists with high selectivity; 3) design, synthesis and evaluation of cycli, conformationally-constrained somatostatin-like peptides with little or no somatostatin activity, but with high potency and specificity for mu opioid receptors; 4) examination in detail of the conformational and dynamic properties of the most potent and selective analogues from 1, 2, and 3 to obtain insight into the rational design of more selective or potent analogues using modern graphics and computational methods; 5) to examine in detail the binding activities of these compounds at mu and delta opioid receptors (the most selective analogues with be radiolabeled and receptor localized in the brain by modern autoradiographic methods); 6) to obtain a comprehensive evaluation of the opioid agonist and antagonist in vitro and in vivo activities of the analogues we have prepared and compare these activities with standard drugs; and 7) to use the above results to design more specific and more potent analogues for the delta and mu receptor. The long term goals of this research are to develop an understanding of the physiological roles of the various opioid receptors, and to develop ligands for these receptors which can be used for the treatment of disease.