NEUROPEPTIDES--MOLECULAR MECHANISM OF ACTION

项目确定了 阿片肽：1.含有/Dmt/和/Tic/的阿片样物质二肽 具有极高的d亲和力（Ki = 0.02 nM）和选择性（Kim/Kid = 150，000）;三肽，含有L-Ala 3，其中/Kim/Kid = 20，000/。 Tyr-Tic同源物与d受体弱相互作用。 意见：㈠ 肽是拮抗剂;（ii）最小的肽， 阿片类药物的性质;（iii）游离酸在C-末端排斥结合从 m受体位点;（iv）L-异构体关键，因为D-Tic降低了d结合 并与酰胺组合产生M选择性肽;和（V）无 与K受体相互作用。 生理数据显示， 是拮抗剂，逆转deltorphin的抗伤害活性 icv或全身暗示通过血雨屏障。 统计分析表明，H-Dmt-Tic-OH符合单位点结合 模型，而H-Dmt-Tic-ol和三肽适合双位点结合 模型2.阿片类药物不忠：具有双重高剂量的新型阿片肽激动剂 对D和M受体的亲和力。3. Deltorphin的设计与合成 在2-4位用非手性Ca，α-二烷基环状物修饰的类似物 α-氨基酸。结果：（I）位置2处的D-异构体对于高 选择性，高亲和力;（ii）高选择性不需要酸功能 亲和力，但仅用于D选择性。

Project determined the physicochemical and bioactivity properties of opioid peptides: 1. Opioidmimetic dipeptides containing /Dmt/ and /Tic/ with extremely high d affinity (Ki = 0.02 nM) and selectivity (Kim/Kid = 150,000); tripeptides, containing L-Ala3, with /Kim/Kid = 20,000/. Tyr-Tic cognates weakly interacted with d receptors. Observations: (i) peptides are antagonists; (ii) smallest peptides to elicit highly potent opioid properties; (iii) free acid at C-terminus repulses binding from m receptor sites; (iv) L-isomer critical, since D-Tic decreased d binding and in combination with amide produced m selective peptides; and (v) none interacted with k receptors. Physiological data revealed that peptides were antagonists, reversing the antinociceptive activity of deltorphin icv or systemically suggesting passage through the blood rain barrier. Statistical analyses indicated that H-Dmt-Tic-OH fits one-site binding models, whereas H-Dmt-Tic-ol and the tripeptides fit two-site binding models. 2. Opioid infidelity:novel opioid peptide agonists with dual high affinity for d and m receptors. 3. Design and synthesis of deltorphin analogues modified at positions 2-4 with achiral Ca,a-dialkyl cyclic a-amino acids. Results: (I) D-isomer at position 2 not essential for high selectivity, high affinity; (ii) acid function not required for high affinity, but only for d selectivity.