Chemical syntheses and biological studies on dimeric chimeras of oxytocin and the V2-antagonist, d(CH2)5[D-Ile2,Ile4]arginine vasopressin
Chemical syntheses and biological studies on dimeric chimeras of oxytocin and the V2-antagonist, d(CH2)5[D-Ile2,Ile4]arginine vasopressin
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DOI：
10.1021/jm9900220
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发表时间：
1999-12-02
影响因子：
7.3
通讯作者：
Barany, G
中科院分区：
文献类型：
--
作者：
Chen, L;Golser, R;Barany, G
将神经垂体激素催产素和强效抗利尿激素V(2)-拮抗剂d(CH(2))(5)[d- Ile(2),Ile(4)]精氨酸抗利尿激素结合成一个单分子的平行和反平行异二聚体已被合成，与N(α)-9-芴基甲基氧羰基（Fmoc）化学相合成，具有适当组合的正交保护基团对巯基[S-（N-甲基-N-苯基氨基甲酰基）磺酰基（Snm）；S-acetamidormethyl (Acm);s -三苯基甲基（Trt）]，用于组装所需的线性非肽酰胺单体中间体，然后通过溶液反应以确定的方式聚集在一起，以提供两种异二聚体。第一个二硫桥是通过一个单体的1- β -巯基- β -环五亚甲基丙酸（Pmp）残基的游离巯基攻击到另一个单体的半胱氨酸残基的Snm基团上形成的；逆定向策略由于位阻而失败。第二个二硫桥是由相邻链上的Cys（Acm）残基碘共氧化形成的。生物学研究表明，平行嵌合体和反平行嵌合体均缺乏加压活性，子宫舒张活性低，利尿活性与单体V(2)拮抗剂相当。钠的排泄取决于实验条件。因此，在4%的水负荷下，两种嵌合体都显示出类似于等摩尔催产素和V(2)拮抗剂混合物的效果，即钠排泄量低于单独使用催产素的结果，但高于单独使用V(2)拮抗剂的结果。然而，当不使用水负荷时，平行嵌合体被证明比单独使用催产素或催产素和V(2)拮抗剂的等摩尔混合物更有效地促进钠排泄。
Parallel and antiparallel heterodimers have been synthesized that combine into a single molecule the neurohypophyseal hormone oxytocin and the potent vasopressin V(2)-antagonist d(CH(2))(5)[D-Ile(2),Ile(4)]arginine vasopressin, Solid-phase synthesis with N(alpha)-9-fluorenylmethyloxycarbonyl (Fmoc) chemistry, featuring appropriate combinations of orthogonal protecting groups for the thiols [S-(N-methyl-N-phenylcarbamoyl)sulfenyl (Snm); S-acetamidormethyl (Acm); S-triphenylmethyl (Trt)], was used to assemble the required linear nonapeptide amide monomer intermediates, which were then brought together in defined ways by solution reactions to provide the two heterodimers. The first disulfide bridge was formed by a directed approach involving attack by the free thiol of the 1-beta-mercapta-beta,beta-cyclopentamethylenepropionic acid (Pmp) residue of one monomer onto the Snm group of a cysteine residue on the other monomer; the inverse directed strategy failed due to steric hindrance. The second disulfide bridge was formed by iodine co-oxidation of Cys(Acm) residues on adjacent chains. Biological studies revealed that both the parallel and antiparallel chimeras lack presser activity, have low uterotonic activity, and have diuretic activities comparable to that of the monomeric V(2)-antagonist, Sodium excretion depends on experimental conditions. Thus, with a 4% water load, both chimeras display effects similar to that of an equimolar mixture of oxytocin and V(2)-antagonist, i.e., lower sodium excretion than that resulting from administration of oxytocin alone but higher than that when V(2)-antagonist was administered alone. However, when no water load was used, the parallel chimera proved to be more effective in promoting sodium excretion than either oxytocin alone or an equimolar mixture of oxytocin and V(2)-antagonist.