NEUROPEPTIDES--MOLECULAR MECHANISM OF ACTION

该项目包括测定其物理化学性质 德吗啡和肾上腺素中的氨基酸残留量，环保 来源于两栖动物的皮肤分泌物；它们表现出高亲和力和 哺乳动物内源性阿片受体的选择性。应用实体 和溶液相肽化学，200多个合成类似物被 使用天然和不寻常的氨基酸制成。受体研究与 对大鼠脑膜的1位和2位点进行了统计分析 通过严格的迭代模式绑定模型：适用于双站点模型 包括Hill系数和0.85，95%置信度的窄对数 区间(，0.10)，P&lt；0.0001。侧链和手性的重要性 对N-末端四肽区域的残基进行了鉴定 分析：例如AIB、ALA或一系列1-氨基环烷-1-羧酸 2到4位的酸表明，在七肽中， 2位的关键D-氨基酸异构体和临界芳香族 3位侧链可被疏水残基消除。 Pro或ABU对阴离子基团的取代表明 负电荷在Delta受体亲和力中起主要作用，尽管 Delta的选择性取决于它的存在。收购5家公司 在某些肾上腺素类似物中的亲和力，与地吗啡相当， 在单一多肽中具有双重亲和力。基于这些推论 数据，我们开发了一系列双肽和三肽的超选择性 代表通用阿片拮抗剂的类阿片肽 其选择性超过任何已知的阿片类药物 规模之大。研究将继续开发新的多肽 激动剂：具有治疗慢性和急性的潜在应用 疼痛，以及治疗麻醉性成瘾、酒精中毒和其他疾病的拮抗剂 临床症状。

This project involved determination of the physicochemical properties of amino acid residues in dermorphins and deltorphins, environmentally derived from amphibian skin secretions; they exhibit high affinity and selectivity for endogenous mammalian opioid receptors. Applying solid and solution phase peptide chemistry, over 200 synthetic analogues were prepared using natural and unusual amino acids. Receptor studies with membranes from rat brain were statistically analyzed for 1- and 2-site binding models by a stringent iterative mode: fits to 2-site models included Hill coefficient < 0.85, narrow log of the 95% confidence interval ( 0.1), P < 0.0001. Importance of the side-chain and chirality of the residues in the N-terminal tetrapeptide region were identified and analyzed: e.g. Aib, Ala, or a series of 1-aminocycloalkane-1-carboxylic acids in positions 2 through 4 revealed that in the heptapeptide, the crucial D-amino acid isomer at position 2 and the critical aromatic side-chain at position 3 could be eliminated by hydrophobic residues. Substitutions of the anionic group by Pro or Abu indicated that the negative charge played a major role in delta receptor affinity, although delta selectivity was dependent on its presence. The acquisition of 5 affinity in some deltorphin analogues, comparable to dermorphin, conferred dual affinity in a single peptide. Based on these culmulative data, we developed a series of di- and tripeptide ultraselective opioidmimetic peptides that represent the universal opioid antagonist message and whose selectivity exceeded that of any known opioid by orders of magnitude. Investigations will continue to develop novel peptide analagues: agonists with potential application for chronic and acute pain, and antagonists to treat narcotic addiction, alcoholism and other clinical syndromes.