RECEPTOR SPECIFIC ENKEPHALIN ANALOGUES

我们建议开发一系列循环和其他构象的 具有高受体选择性、高选择性的限制性多肽类似物 激动剂或拮抗剂效力强，体内稳定性高，持续时间长 Delta和Mu阿片受体活性。为此，我们的计划 利用多学科方法结合现代合成氨基酸 和多肽化学、构象分析、动力学和多肽药物 设计，包括生化、生物物理、生理和行为 药理学。我们的具体目标包括：1)设计、综合和 新型脑啡肽类似物与Delta阿片受体激动剂的评价 活性和选择性；2)阿片受体的研究进展 具有高选择性的拮抗剂；3)设计、合成和评价 环，构象受限的生长抑素样肽，几乎没有 或无生长抑素活性，但对MU具有高效力和特异性 阿片受体；4)详细检查构象和 最有效和选择性最强的类似物1，2， 以及3洞察更具选择性或更具代表性的 使用现代图形学和计算方法的有效模拟；5) 详细考察这些化合物在微米和三角洲的结合活性。 阿片受体(选择性最高的类似物，具有放射性标记和 通过现代放射自显影方法定位于大脑中的受体)；6) 获得阿片类激动剂和拮抗剂的综合评价 我们制备的类似物的体内外活性比较 这些活动与标准药物有关；以及7)利用上述结果 为三角洲和MU设计更具体、更强大的类似物 受体。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，可用于 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.