Synthesis of potent heptapeptide analogues of cholecystokinin.
Synthesis of potent heptapeptide analogues of cholecystokinin.
复制标题
胆囊收缩素的有效七肽类似物的合成。
DOI：
10.1021/jm00373a006
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发表时间：
1984
影响因子：
7.3
通讯作者：
Rivier,J
中科院分区：
文献类型：
--
作者：
Penke,B;Hajnal,F;Lonovics,J;Holzinger,G;Kadar,T;Telegdy,G;Rivier,J
用固相合成法合成了9个新的乙酰基-CCK-七肽类似物(Ac-Tyr(S03H)2-Met3-Gly4-Trp5-Met67-Asp7-Phe8-NH2)。在第一个系列中，Asp7残基被羟基氨基酸硫酸酯取代。在另一个系列中，Gly4被D-Ala取代，Trp5和Met6被它们的D对映体取代。硫酸酯的引入是用一种新的温和、结晶和稳定的试剂--乙酰硫酸吡啶进行的。在体外实验中，7位含有酪氨酸(SOSH)2和羟基氨基酸硫酸酯[Ser(S03H)、Thr(SG3H)或Hyp(S03H)L]的类似物的药效分别是CCK-8的1.9、1.7和3.0倍。虽然在体内缺乏胃泌素样活性，但这些类似物具有强大的抗惊厥活性。含有D-氨基酸残基的类似物在体外的效力低于母体化合物。然而，D-Ala4替代物在体外试验中产生的化合物的效力是CCK-8的40%，但对Oddi括约肌的作用持续时间更长。虽然7-取代的Ac-CCK七肽是迄今为止报道的最有效的CCK类似物之一，但D-Ala4取代首次导致了体内活性的延长。胃肠激素CCK-胰酶以不同的分子形式存在，包括CCK-39、CCK-33、CCK-12和CCK-8.1所有具有生物活性的CCK片段都在第27位含有酪氨酸O-硫酸盐。分子的活性中心是C端的七肽2(CCK-27-33或CCK-7)，但天然存在的最短的生物活性片段是C端的八肽3(CCK-26-33或CCK-8)。4然而，CCK-7的N末端氨基不是胆囊动力活动所必需的，5同样，CCK-7的IV-乙酰衍生物在胰腺淀粉酶释放试验中显示出与CCK-8相同的效力。6在这些观察和早期研究7的基础上，证明了四氢胃泌素(H-G)的天冬氨酸残基。
Nine new analogues of acetyl-CCK-heptapeptide (Ac-Tyr (S03H) 2-Met3-Gly4-Trp5-Met6 7-Asp7-Phe8-NH2) were synthesized by solid-phase methodology. In a first series, the Asp7 residue was replaced by hydroxy amino acid sulfate esters. In another series, Gly4 was substituted by D-Ala, while Trp5 and Met6 were replaced bytheir D enantiomer. The introduction of the sulfate ester was performed with a new, mild, crystalline, and stable reagent, pyridinium acetyl sulfate. Each analogue that contained Tyr (SOsH) 2 and a hydroxy amino acid sulfate ester [Ser (S03H), Thr (SG3H), or Hyp (S03H) l in position 7 proved to be more potent (1.9, 1.7, and 3.0 times, respectively) than CCK-8 in vitro (isolated gallbladder strips). While devoid of gastrin-like activity in vivo, these analogues had potent anticonvulsive activity. The analogues containing a D-amino acid residue were less potent than the parent compound in vitro. The D-Ala4 replacement, however, yielded a compound that was 40% as potent as CCK-8 in the in vitro test but showed prolonged duration of action on sphincter Oddi. While the 7-substituted Ac-CCK heptapeptides are among the most potent CCK analogues reported so far, the D-Ala4 replacement resulted, for the first time, in prolonged activity in vivo.The gastrointestinal peptide hormone cholecystokinin-pancreozymin exists indifferent molecular forms, including CCK-39, CCK-33, CCK-12, and CCK-8.1 All biologically active CCK fragments contain a tyrosine O-sulfate in position 27. The active center of the molecule is the C-terminal heptapeptide2 (CCK-27-33 or CCK-7), but the shortest naturally occurring biologicallyactive fragment is the C-terminal octapeptide3 (CCK-26-33 or CCK-8). 4 The N-terminal amino group of CCK-7, however, is not necessary for cholecystokinetic activity, 5 and similarly, the iV-acetyl derivative of CCK-7 shows the same potency as CCK-8 in the pancreas amylase release test. 6 Onthe basis of these observations and an earlier study7 that demon-strated that the aspartyl residue of the tetragastrin (H-