Rekka E, Sterk G J, Timmerman H, Bast A
Department of Pharmacochemistry, Faculty of Chemistry, Vrije Universiteit, Amsterdam, The Netherlands.
Chem Biol Interact. 1988;67(1-2):117-27. doi: 10.1016/0009-2797(88)90091-9.
Several potential H2-receptor antagonists have been tested in vitro, using liver microsomal preparations from untreated rats, in order to study their interaction with P-450. The aim of this investigation was to establish structure-activity relationships for the P-450-inhibition developed by cimetidine and related drugs. Most of the compounds tested demonstrate an inhibitory activity and a binding ability to P-450, via type II (ligand type) binding. Our results strongly indicate that the cyano-guanidine moiety is an essential structural feature for both the inhibition of a ferrocytochrome P-450-metabolic intermediate complex formation occurring during the metabolism of tofenacine, and the binding of the compounds to the heme iron of P-450. The presence of an imidazole group is not necessary for these activities. Furthermore, it is pointed out that the lipophilic character of the cyano-guanidine side chain contributes to the interaction of the test compounds with P-450, since a trend for a parabolic relationship between lipophilicity and inhibitory activity or binding ability is observed. Finally, under the experimental conditions used, no increase of the inhibitory activity of cimetidine on the metabolism of tofenacine and 7-ethylresorufin is observed after preincubation of rat liver microsomes with cimetidine, confirming earlier results in similar studies.
为了研究几种潜在的H2受体拮抗剂与P-450的相互作用，已使用未处理大鼠的肝微粒体制剂在体外进行了测试。本研究的目的是建立西咪替丁及相关药物对P-450抑制作用的构效关系。大多数测试化合物通过II型（配体类型）结合表现出对P-450的抑制活性和结合能力。我们的结果有力地表明，氰基胍部分是抑制托芬那辛代谢过程中发生的亚铁细胞色素P-450代谢中间复合物形成以及化合物与P-450血红素铁结合的必需结构特征。这些活性并不需要咪唑基团的存在。此外，需要指出的是，氰基胍侧链的亲脂性有助于测试化合物与P-450的相互作用，因为观察到亲脂性与抑制活性或结合能力之间呈抛物线关系的趋势。最后，在所用的实验条件下，大鼠肝微粒体与西咪替丁预孵育后，未观察到西咪替丁对托芬那辛和7-乙基试卤灵代谢的抑制活性增加，这证实了早期类似研究的结果。
