Huffman W F, Albrightson-Winslow C, Brickson B, Bryan H G, Caldwell N, Dytko G, Eggleston D S, Kinter L B, Moore M L, Newlander K A
Department of Peptide Chemistry, Smith Kline & French Laboratories, King of Prussia, Pennsylvania 19406.
J Med Chem. 1989 Apr;32(4):880-4. doi: 10.1021/jm00124a025.
[1-(beta,beta-Pentamethylene-beta-mercaptopropionic acid),2-(O-ethyl)-D- tyrosine,4-valine,9-desglycine]arginine-vasopressin (SK&F 101926, 1), a potent in vivo and in vitro vasopressin V2 receptor antagonist, was recently tested in human volunteers and shown to be a full antidiuretic agonist. A new animal model for vasopressin activity has been developed in dogs that duplicates the clinical agonist findings exhibited with SK&F 101926. In this model we have discovered that substitution of a cis-4'-methyl group on the Pmp moiety at residue 1 of vasopressin antagonists results in substantially reduced agonist activity compared to the unsubstituted molecule (SK&F 101926). The corresponding analogue with a trans-4'-methyl group exhibits more agonist activity than the cis molecule. These findings can be explained by viewing the biological activities of compounds such as 1 as the interaction of the vasopressin receptor with a number of discrete molecular entities, conformers of 1, which present different pharmacophores. Models have been developed to assist in the understanding of these results.
[1-(β,β-亚戊基-β-巯基丙酸),2-(O-乙基)-D-酪氨酸,4-缬氨酸,9-去甘氨酸]精氨酸加压素(SK&F 101926, 1)是一种强效的体内和体外加压素V2受体拮抗剂，最近在人类志愿者中进行了测试，结果显示它是一种完全的抗利尿激动剂。已经在犬类中建立了一种新的加压素活性动物模型，该模型重现了SK&F 101926所表现出的临床激动剂结果。在这个模型中，我们发现，与未取代的分子(SK&F 101926)相比，在加压素拮抗剂第1位残基的Pmp部分上取代一个顺式-4'-甲基基团会导致激动剂活性大幅降低。具有反式-4'-甲基基团的相应类似物比顺式分子表现出更多的激动剂活性。通过将诸如1这样的化合物的生物活性视为加压素受体与许多离散的分子实体(1的构象异构体)的相互作用来解释这些发现，这些构象异构体呈现出不同的药效基团。已经开发出模型来帮助理解这些结果。
