Potent morphiceptin analogs: structure activity relationships and morphine-like activities.
Potent morphiceptin analogs: structure activity relationships and morphine-like activities.
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发表时间：
1983-11
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通讯作者：
K. Chang;E. Wei;A. Killian;J. Chang
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作者：
K. Chang;E. Wei;A. Killian;J. Chang
Morphiceptin (Tyr-Pro-Phe-Pro-NH2) 是一种非脑啡肽，是一种对 mu 阿片受体具有高度选择性的阿片受体激动剂。通过在残基 2、3 和 4 处取代结构相关的氨基酸，对 Tyr-Pro-Phe-Pro-NH2 进行化学修饰。然后使用 125I 标记的 FK 33,824 (Tyr-D-Ala-Gly-NMePhe-Met(O)-ol) 作为 mu 配体和 125I 标记，检查合成的吗啡肽类似物的受体结合活性。 D-Ala2,D-Leu5-脑啡肽作为 δ-配体，对小鼠输精管电诱发平滑肌收缩和豚鼠回肠离体肌间丛纵向肌条具有抑制活性。所有这些类似物在δ阿片受体结合位点实际上没有表现出活性。苯丙氨酸氮原子的甲基化以及 L-脯氨酸 C 端被 D-脯氨酸取代产生了有效的 mu 激动剂，原型类似物是 Tyr-Pro-NMePhe-D-Pro-NH2 (PL017)。吗啡肽及其类似物与 mu 受体结合的 IC50 值与豚鼠回肠试验中的 ED50 值相关，表明回肠效应是由 mu 受体相互作用介导的。小鼠输精管测定中 mu 受体结合活性与 ED50 值之间的类似相关性表明吗啡肽及其类似物也作用于该组织中的 mu 受体。这一观点得到了观察结果的支持，即纳洛酮在小鼠输精管中相对于 PL017 具有 8.71 的高 pA2 值。在体内研究中，将 PL017 集中注射到第四脑室的头侧部分，可在大鼠体内产生持久的纳洛酮可逆镇痛作用。（摘要截短为 250 字）
Morphiceptin (Tyr-Pro-Phe-Pro-NH2), a nonenkephalin peptide, is an opioid agonist highly selective for mu opiate receptors. Chemical modification of Tyr-Pro-Phe-Pro-NH2 was carried out by substituting structurally related amino acids at residues 2, 3 and 4. The morphiceptin analogs synthesized were then examined for receptor binding activities using 125I-labeled FK 33,824 (Tyr-D-Ala-Gly-NMePhe-Met(O)-ol) as the mu-ligand and 125I-labeled D-Ala2,D-Leu5-enkephalin as the delta-ligand, and for inhibitory activities on electrically evoked smooth muscle contraction of mouse vas deferens and isolated myenteric plexus-longitudinal muscle strips of guinea-pig ileum. All of these analogs showed virtually no activity at delta opiate receptor binding sites. Methylation of the nitrogen atom of phenylalanine and the substitution at the C-terminal of L-proline by D-proline produced potent mu-agonists, the prototype analog being Tyr-Pro-NMePhe-D-Pro-NH2 (PL017). The IC50 values of morphiceptin and its analogs for mu receptor binding were correlated to the ED50 values in the guinea-pig ileum assay, suggesting that the ileum effects were mediated by mu receptor interactions. A similar correlation between mu receptor binding activity and the ED50 values in the mouse vas deferens assay suggested that morphiceptin and its analogs also acted on mu receptors in this tissue. This idea is supported by the observation that naloxone has a high pA2 value of 8.71 against PL017 in mouse vas deferens. In in vivo studies, PL017 administered centrally into the rostral portion of the 4th ventricle produced long-lasting, naloxone-reversible analgesia in rats.(ABSTRACT TRUNCATED AT 250 WORDS)