Inhibition of gastric H+,K+-ATPase and acid secretion by SCH 28080, a substituted pyridyl(1,2a)imidazole.
Inhibition of gastric H+,K+-ATPase and acid secretion by SCH 28080, a substituted pyridyl(1,2a)imidazole.
复制标题
DOI：
10.1016/s0021-9258(18)61620-5
复制
发表时间：
1987-02
期刊：
影响因子：
--
通讯作者：
B. Wallmark;Carin BrivingS;Jan FryklundS;Keith MunsonQ;Raymond Jacksons;John MendleinQ;Edd RabonQ;George SachsQ
中科院分区：
文献类型：
--
作者：
B. Wallmark;Carin BrivingS;Jan FryklundS;Keith MunsonQ;Raymond Jacksons;John MendleinQ;Edd RabonQ;George SachsQ
一种疏水性胺，SCH 28080，2-甲基-8-(苯基甲氧基)咪唑(1,2a)吡啶-3-乙腈，先前已被证明可在体内和体外抑制胃酸分泌，当使用组胺、高 K+ 浓度或二丁酰 cAMP 作为促分泌剂时，也可抑制离体胃腺中的基础和刺激的氨基比林积累。刺激耗氧量（而非基础耗氧量）也受到抑制。高浓度弱碱咪唑中和壁细胞的酸性空间，降低了药物的效力，表明 SCH 28080 在质子化时具有活性。对分离的 H+,K+-ATP 酶的研究表明，无论使用 ATP 还是磷酸对硝基苯酯作为底物，该化合物都能与 K+ 竞争性抑制该酶。相反，对磷酸对硝基苯酯的抑制作用是混合的，并且对 ATP 的抑制作用不具有竞争性。该药物降低了磷酸酶的稳态水平，但没有降低在缺乏 K+ 的情况下观察到的磷酸酶形成的速率常数，也没有降低与 K+ 反应的磷酸酶的数量。该药物可猝灭异硫氰酸荧光素修饰酶的荧光，并抑制 H+,K+-ATP 酶的不依赖于 ATP 的 K+ 交换反应。其对胃酸分泌的作用可以通过与酶的可逆络合来抑制 H+,K+-ATP 酶来解释。因此，此类化合物充当胃酸分泌的可逆抑制剂。
A hydrophobic amine, SCH 28080, 2-methyl-8-(phenylmethoxy)imidazo(1,2a)pyridine-3-acetonitrile, previously shown to inhibit gastric acid secretion in vivo and in vitro, was also shown to inhibit basal and stimulated aminopyrine accumulation in isolated gastric glands when histamine, high K+ concentrations, or dibutyryl cAMP were used as secretagogues. Stimulated, but not basal, oxygen consumption was also inhibited. Neutralization of the acid space of the parietal cell by high concentrations of the weak base, imidazole, reduced the potency of the drug, suggesting that SCH 28080 was active when protonated. Studies on the isolated H+,K+-ATPase showed that the compound inhibited the enzyme competitively with K+, whether ATP or p-nitrophenyl phosphate were used as substrates. In contrast, the inhibition was mixed with respect to p-nitrophenyl phosphate and uncompetitive with respect to ATP. The drug reduced the steady state level of the phosphoenzyme but not the observed rate constant for phosphoenzyme formation in the absence of K+ nor the quantity of phosphoenzyme reacting with K+. The drug quenched the fluorescence of fluorescein isothiocyanate-modified enzyme and also inhibited the ATP-independent K+ exchange reaction of the H+,K+-ATPase. Its action on gastric acid secretion can be explained by inhibition of the H+,K+-ATPase by reversible complexation of the enzyme. This class of compound, therefore, acts as a reversible inhibitor of gastric acid secretion.