Synthesis and Activity of Novel Kappa Opioid Peptides

描述(由申请人提供) 强啡肽A是一种内源性神经肽，具有很高的亲和力和选择性 用于kappa阿片受体。据报道，N-末端 ？留言？序列对kappa阿片受体激活很重要，而kappa阿片受体 ？地址？序列被指定为负责增强效力的结构域 由于强啡肽A的高度特异性，两个新的先导Dyn A类似物，arodyn (芳香族强啡肽)和JVA-901表现出不同的构效关系 因此，假设Arodyn和JVA-901 以不同的方式与kappa阿片受体结合。这项研究的目的是 建议确定有效和选择性的kappa阿片受体拮抗剂。 为了实现这一目标，将设计新的选择性kappa受体拮抗剂 利用经典多肽和组合多肽文库，并使用 中国仓鼠卵巢细胞稳定表达阿片受体。组合在一起 将使用经典和组合方法来修改序列 对上述两个先导肽进行筛选，并生成聚焦多肽文库。 组合多肽文库提供了合成各种不同 同时合成多肽，并允许引入各种组合 Arodyn和JVA-901序列中的氨基酸。将会进行合成 采用固相法合成多肽。有很多潜在的临床应用 Kappa激动剂和拮抗剂的应用，包括预防 胰腺炎，神经保护(癫痫)和抗惊厥药，潜力 可卡因滥用和阿片依赖的治疗以及在 药理学检测作为帮助理解kappa的药理学工具 Kappa选择性以来受体-配体在分子水平上的相互作用 多肽拮抗剂是有限的。

DESCRIPTION (provided by applicant) Dynorphin A, an endogenous neuropeptide, is has high affinity and selectivity for the kappa opioid receptors. It has been reported that the N-terminus ?message? sequence is important for kappa opioid receptor activation while the ?address? sequence is designated as the potency-enhancing domain responsible for the high specificity of dynorphin A. Two novel lead Dyn A analogues, arodyn (aromatic dynorphin), and JVA-901, have displayed different structure-activity relationships from Dyn A. It is therefore hypothesized that arodyn and JVA-901 bind differently to the kappa opioid receptors. The goal of this research proposal is to identify potent and selective kappa opioid receptor antagonists. To pursue this goal novel selective kappa receptor antagonists will be designed utilizing classic and combinatorial peptide libraries and evaluated using Chinese hamster ovary cells stably expressing opioid receptors. The combination of classical and combinatorial approaches will be used to modify the sequences of the two aforementioned lead peptides and generate focused peptide libraries. Combinatorial peptide libraries offer the advantage of synthesizing a variety of peptides simultaneously and allows the introduction of various combinations of amino acids in the sequence of arodyn and JVA-901. Syntheses will be done using solid phase peptide synthesis. There are many potential clinical applications of kappa agonists and antagonists, including the prevention of pancreatitis, neuroprotection (epilepsy) and anti-convulsants, potential treatment in cocaine abuse and opioid dependence as well as use in pharmacological assays as pharmacological tools to help understand kappa receptor-ligand interactions at the molecular level since kappa-selective peptide antagonists are limited.