Bregman M D, Trivedi D, Hruby V J
J Biol Chem. 1980 Dec 25;255(24):11725-31.
Using native glucagon and [12-homoarginine]glucagon (analogue A), prepared in high yield and purity by new procedures, we have synthesized the following glucagon analogues by semisynthetic methods: [1-deshistidine][12-homoarginine]glucagon (analogue B); N alpha-carbamoylglucagon (analogue C); N alpha, N epsilon-dicarbamoylglucagon (analogue D); [1-N alpha-carbamoylhistidine, 12-N epsilon-trinitrophenyllsyine]glucagon (analogue II); [1-deshistidine] [2-N alpha-trinitrophenylserine, 12-homoarginine]glucagon (analogue III); and [1-N alpha-trinitrophenylhistidine, 12-homoarginine]glucagon (analogue IV). The introduction of hydrophylic groups at the alpha- and epsilon-amino positions of glucagon results in a reduction in potency. The alpha-position is also involved in biological activity. Carbamylation of the alpha-position results in a partial agonist (analogues C and D). The introduction of hydrophobic groups and the neutralization of the positive charge at the alpha- and epsilon-amino positions result in glucagon antagonists (analogues II, III, and IV). [1-N alpha-Trinitrophenylhistidine, 12-homoarginine]glucagon (analogue IV) is the most potent inhibitor tested. Based on its competitive inhibitory action, this analogue appears to have about one-third the affinity of glucagon for the receptor site. These modifications at the epsilon-amino position cause an increase in the secondary structure of the peptide (as shown by circular dichroism studies) which may be related to their biological activities.
我们采用新方法以高产率和高纯度制备了天然胰高血糖素和[12-高精氨酸]胰高血糖素（类似物A），并通过半合成方法合成了以下胰高血糖素类似物：[1-去组氨酸][12-高精氨酸]胰高血糖素（类似物B）；Nα-氨基甲酰基胰高血糖素（类似物C）；Nα，Nε-二氨基甲酰基胰高血糖素（类似物D）；[1-Nα-氨基甲酰基组氨酸，12-Nε-三硝基苯赖氨酰]胰高血糖素（类似物II）；[1-去组氨酸][2-Nα-三硝基苯丝氨酰，12-高精氨酸]胰高血糖素（类似物III）；以及[1-Nα-三硝基苯组氨酸，12-高精氨酸]胰高血糖素（类似物IV）。在胰高血糖素的α-和ε-氨基位置引入亲水基团会导致活性降低。α-位置也参与生物活性。α-位置的氨甲酰化产生部分激动剂（类似物C和D）。引入疏水基团并中和α-和ε-氨基位置的正电荷会产生胰高血糖素拮抗剂（类似物II、III和IV）。[1-Nα-三硝基苯组氨酸，12-高精氨酸]胰高血糖素（类似物IV）是所测试的最有效的抑制剂。基于其竞争性抑制作用，该类似物对受体位点的亲和力似乎约为胰高血糖素的三分之一。在ε-氨基位置的这些修饰导致肽的二级结构增加（如圆二色性研究所示），这可能与其生物活性有关。
