Synthesis and biological activity of beta-endorphin and analogues. Additional evidence for multiple opiate receptors.
Synthesis and biological activity of beta-endorphin and analogues. Additional evidence for multiple opiate receptors.
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β-内啡肽及其类似物的合成和生物活性。
DOI：
10.1021/jm00210a012
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发表时间：
1978
影响因子：
7.3
通讯作者：
S. St. Pierre
中科院分区：
文献类型：
--
作者：
S. Lemaire;A. Bérubé;G. Derome;I. Lemaire;J. Magnan;D. Regoli;S. St. Pierre
据报道，[D-Ala2，MePhe4]-和[D-Ala2，MePhe4，Met (0) 5]-/3s-内啡肽。通过多项分析标准以及三项生物测试，发现合成/3s-内啡肽与天然激素相同。合成化合物的相对效力通过其抑制豚鼠回肠和输精管电诱发收缩的能力以及与氚化纳洛酮竞争大鼠脑匀浆上的阿片受体的能力来估计。在 ds-内啡肽的 2 位引入 D-Ala 会导致其在大鼠输精管生物测定中的活性增加 58%，而在其他两种生物测定中，其活性略有下降。用A''-甲基苯丙氨酸替换[o-Ala2]-Js-内啡肽中的Phe4，在大鼠输精管和[3H]纳洛酮结合试验中，ds-内啡肽的活性分别增加2.6倍和1.4倍，而豚鼠回肠生物测定发现活性急剧下降。 MePhe4]-/3s-内啡肽在第 5 位引入 Met (O)，不会引起母肽生物活性的任何额外变化。ds-内啡肽的特定修饰引起的反应异质性强烈表明存在不止一种类型的阿片肽受体。自从发现内源性吗啡样肽、脑啡肽 1'2 和内啡肽后，3” 5。为了设计具有更强活性和更持久作用的脑啡肽类似物，已经完成了大量工作。然而，对于较大的肽 3-内啡肽的研究相对较少，人们发现它是最有效的、天然存在的阿片肽，当中央注射时可产生镇痛4、6''和低温8。
[D-Ala2, MePhe4]-, and [D-Ala2, MePhe4, Met (0) 5]-/3s-endorphins, is reported. Synthetic/3s-endorphin was found identical with the natural hormone by several analytical criteria as well as by three biological tests. Relative potencies of the synthetic compounds were estimated by their ability to inhibit the electrically evoked contractions of the guinea pig ileum and of therat vas deferens and to compete with tritiated naloxone for opiate receptors on rat brain homogenates. Introduction of D-Ala in position 2 of ds-endorphin induces a 58% increase in its activity with the rat vas deferens bioassav and a slight decrease in its activity with the two other bioassays. Replacement of Phe4 in [o-Ala2]-Js-endorphin by A'“-methylphenylalanine results in a respective 2.6-and 1.4-fold increase in the activity of, ds-endorphin with the rat vas deferens and [3H] naloxonebinding tests, whereas a dramatic decrease in the activity was found with the guinea pig ileum bioassay. Further substitution of [D-Ala2, MePhe4]-/3s-endorphin, introducing Met (O) in position 5, doesnot induce any additional change in the biological activity of the parentpeptide. The heterogeneity of responses caused by a specific modification in ds-endorphin strongly suggests the existence of more than one type of receptor for the opioid peptide.Since the discoveryof endogenous morphine-like peptides, the enkephalins1’2 and the endorphins, 3” 5 much work has been accomplished to design analogues of enkephalin with stronger activity and longer lasting effects. However, relatively little work has yet been done with the larger peptide,/3-endorphin, which was found to be the most potent, naturally occurring opioid peptide inpro-ducing analgesia4, 6’’and hypothermia8 when injected centrally.