New antagonists of LHRH. II. Inhibition and potentiation of LHRH by closely related analogues.
New antagonists of LHRH. II. Inhibition and potentiation of LHRH by closely related analogues.
复制标题
LHRH 的新拮抗剂。
DOI：
10.1111/j.1399-3011.1988.tb01373.x
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发表时间：
1988
期刊：
影响因子：
--
通讯作者：
Schally,AV
中科院分区：
文献类型：
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作者：
Bajusz,S;Csernus,VJ;Janaky,T;Bokser,L;Fekete,M;Schally,AV
对先前描述的LHRH拮抗剂[Ac‐d‐Nal(2)1,d‐Phe(4Cl)2,d‐Trp3,d‐Cit6，d‐Ala10]LHRH和相应的‐hci6类似物进行了修饰，以改变theN‐末端乙酰三肽部分的疏水性。用疏水性较弱的- Pal(3)取代d‐trp3对d‐Cit/d‐hci6类似物的拮抗活性和受体结合能力只有边际效应，但它似乎进一步提高了d‐Cit/d‐hci6替代的毒性降低效果。含有d‐Pal(3)3和d‐Cit/d‐Hci6残基的拮抗剂，即[Ac‐d‐Nal(2)1,d‐Phe(4Cl)2,d‐Pal(3)3d‐Cit6,d‐Ala10]LHRH （SB‐75）和[Ac‐d‐Nal(2)1,d‐Phe(4Cl)2,d‐Pal(3)3,d‐Hci6,d‐Ala10]LHRH (SB‐88)，完全没有毒性作用，如导致死亡的发紫和呼吸抑制，这些毒性作用已在使用了d‐Trp3，d‐arg6拮抗剂和相关拮抗剂的大鼠中观察到。用亲水性氨基甲酰取代theN -乙酰基导致拮抗活性略有下降，尤其是在体外。引入氨基甲酸乙酯型酰基，如甲氧羰基（Moc）或丁氧羰基（Boc），可以得到具有LHRH增强作用的类似物。这些类似物，例如[Moc‐d‐Nal(2)1,d‐Phe(4Cl)2,d‐Trp3,d‐Cit6，d‐Ala10]LHRH和[Boc‐d‐Phe1，d‐Phe(4Cl)2,d‐Pal(3)3,d‐Cit6，d‐Ala10]LHRH诱导的效力增加了170‐260%，并且在过度使用的大鼠垂体系统中持续了2小时以上。
Modifications of the previously described LHRH antagonists, [Ac‐d‐Nal(2)1,d‐Phe(4Cl)2,d‐Trp3,d‐Cit6,d‐Ala10]LHRH and the correspondingd‐Hci6analogue, have been made to alter the hydrophobicity of theN‐terminal acetyl‐tripeptide portion. Substitution ofd‐Trp3with the less hydrophobicd‐Pal(3) had only marginal effects on the antagonistic activities and receptor binding potencies of thed‐Cit/d‐Hci6analogues, but it appeared to further improve the toxicity lowering effect ofd‐Cit/d‐Hci6substitution. Antagonists containingd‐Pal(3)3andd‐Cit/d‐Hci6residues, i.e. [Ac‐d‐Nal(2)1,d‐Phe(4Cl)2,d‐Pal(3)3d‐Cit6,d‐Ala10]LHRH (SB‐75) and [Ac‐d‐Nal(2)1,d‐Phe(4Cl)2,d‐Pal(3)3,d‐Hci6,d‐Ala10]LHRH (SB‐88), were completely free of the toxic effects, such as cyanosis and respiratory depression leading to death, which have been observed in rats with thed‐Trp3,d‐Arg6antagonist and related antagonists. Replacement of theN‐acetyl group with the hydrophilic carbamoyl group caused a slight decrease in antagonistic activities, particularlyin vitro.Introduction of urethane type acyl group such as methoxycarbonyl (Moc) or t‐butoxycarbonyl (Boc) led to analogues that showed LHRH‐potentiating effect. The increase in potency induced by these analogues, e.g. [Moc‐d‐Nal(2)1,d‐Phe(4Cl)2,d‐Trp3,d‐Cit6,d‐Ala10]LHRH and [Boc‐d‐Phe1,d‐Phe(4Cl)2,d‐Pal(3)3,d‐Cit6,d‐Ala10]LHRH, was 170‐260% and persisted for more than 2 h when studied in a superfused rat pituitary system.