potency. Rank order of antagonist potency as a function of dimerization position is as follows: rat uterus, 6 greater than 5 greater than 0 greater than 2 greater than 1 greater than 3 much greater than 4, 7, 8, 9; guinea pig ileum, 6 greater than 5 greater than 3 greater than 2 greater than 1 greater than 0 much greater than 4, 7, 8, 9. Evaluation of the linker length as represented by the number of methylene
对
缓激肽(BK)拮抗剂D-Arg0-Arg1-Pro2-Hyp3-Gly4-Phe5-Ser6-D-Phe 7-Leu8-Arg9的二聚化进行了系统研究。该研究的第一部分涉及化合物,其中通过用半胱
氨酸顺序替换每个
氨基酸并与双马来
酰亚胺基己烷交联来进行二聚化。这项研究的第二部分利用了一系列的双琥珀
酰亚胺基
烷烃二聚体,其中中间的亚甲基链系统地从n = 2变为n = 12,而二聚化的点在位置6保持不变。在两种不同的分离组织制剂中,BK诱导的平滑肌收缩:豚鼠回肠(G
PI)和大鼠子宫(RU)。几种二聚体BK拮抗剂表现出卓越的活性和长效作用。另外,在4、7、8或9位的二聚化产生具有显着降低的效力的二聚体类似物。拮抗剂效价作为二聚化位置的函数的等级次序如下:大鼠子宫,大于6的6大于5,大于2的大于2,大于1的大于3,大于3的大于4、7、8、9;豚鼠回肠,大于6大于5大于3大于2大于1大于0大于4、7、8