Hoffman J M, Pietruszkiewicz A M, Habecker C N, Phillips B T, Bolhofer W A, Cragoe E J, Torchiana M L, Lumma W C, Baldwin J J
J Med Chem. 1983 Feb;26(2):140-4. doi: 10.1021/jm00356a005.
Two series of compounds related to cimetidine and tiotidine were synthesized as part of a study to evaluate the importance of conformational parameters in binding at histamine H2 receptors. The flexible methylthioethyl connecting chain was replaced by a conformationally restricting phenylene unit. These compounds were evaluated for antagonism of the dimaprit-stimulated chronotropic response in the guinea pig atrium and inhibition of histamine stimulated secretion of gastric acid in the dog. In both series, biological activity is markedly dependent on the m-phenylene regioisomers. Histamine H2-receptor activity is retained in both series; however, in the tiotidine series, gastric antisecretory activity is significantly improved. Regardless of the end group, N-cyanoguanidine 1,1-diamino-2-nitroethene or 3,4-diamino-1,2,5-thiadiazole 1-oxide, each 3 3-(2-guanidino-4-thiazolyl)phenyl analogue was ca. 8 and 90 times more potent intravenously than tiotidine and cimetidine, respectively. The electronic influences of the phenylene unit on biological activity were also evaluated. It was concluded that the geometric constraints imposed by the m-phenylene connecting element were more important than electronic factors in binding events at the histamine H2 receptor.
作为评估构象参数在组胺H2受体结合中重要性研究的一部分，合成了与西咪替丁和替奥替丁相关的两类化合物。柔性甲硫基乙基连接链被构象受限的亚苯基单元取代。对这些化合物进行了评估，考察其对豚鼠心房中二甲双胍刺激的变时反应的拮抗作用以及对犬组胺刺激的胃酸分泌的抑制作用。在这两类化合物中，生物活性均明显依赖于间亚苯基区域异构体。两类化合物均保留了组胺H2受体活性；然而，在替奥替丁类化合物中，胃抗分泌活性显著提高。无论端基如何，即N - 氰基胍、1,1 - 二氨基 - 2 - 硝基乙烯或3,4 - 二氨基 - 1,2,5 - 噻二唑1 - 氧化物，每种3 - (2 - 胍基 - 4 - 噻唑基)苯基类似物静脉注射时的效力分别约为替奥替丁和西咪替丁的8倍和90倍。还评估了亚苯基单元对生物活性的电子影响。得出的结论是，在组胺H2受体的结合事件中，间亚苯基连接元件施加的几何限制比电子因素更重要。
