Keeling D J, Laing S M, Senn-Bilfinger J
Smith Kline & French (Research) Ltd., Welwyn, Herts, U.K.
Biochem Pharmacol. 1988 Jun 1;37(11):2231-6. doi: 10.1016/0006-2952(88)90586-2.
SCH 28080 (2-methyl-8-(phenylmethoxy)imidazo[1,2-a] pyridine-3-acetonitrile) is an effective inhibitor of acid secretion in vivo and is a reversible, K+-competitive inhibitor of the gastric (H+ + K+)-ATPase in vitro. The actions of SCH 28080 have been studied on gastric vesicle preparations containing the (H+ + K+)-ATPase. At pH 7, inhibition was competitive with respect to K+ for both ATPase (Ki = 24 nM) and pNPPase (Ki = 275 nM) activities. A close analogue of SCH 28080 (methylated in the 1-N position), that was not expected to cross membranes freely, inhibited ATPase and pNPPase activity less effectively in intact vesicle preparations, where the lumenal (extracellular) face of the membrane was not directly accessible. This suggested that SCH 28080 inhibited both enzyme activities at a lumenal site on the enzyme. Being a protonatable weak base (pKa = 5.6), SCH 28080 would be expected to accumulate on the lumenal, acidic side of the parietal cell membrane in its protonated form. The potency of SCH 28080, relative to that of the "non-protonatable" analogue, increased at low pH, commensurate with the proportion of SCH 28080 in the protonated form. Thus the accumulating protonated form was the active inhibitory species. SCH 28080 (50 nM) blocked the rapid, K+-stimulated dephosphorylation of the catalytic phosphoenzyme intermediate of the (H+ + K+)-ATPase at room temperature. At 4 degrees, higher concentrations of the inhibitor were required, suggesting that the rate of inhibitor binding was slow at low temperatures.
SCH 28080（2-甲基-8-（苄氧基）咪唑并[1,2-a]吡啶-3-乙腈）是一种有效的体内胃酸分泌抑制剂，在体外是胃（H⁺+K⁺）-ATP酶的可逆性、K⁺竞争性抑制剂。已对含有（H⁺+K⁺）-ATP酶的胃小泡制剂研究了SCH 28080的作用。在pH 7时，对于ATP酶（Ki = 24 nM）和对硝基苯磷酸酶（pNPPase，Ki = 275 nM）活性而言，抑制作用相对于K⁺是竞争性的。SCH 28080的一种紧密类似物（在1-N位甲基化），预计不能自由穿过膜，在完整小泡制剂中对ATP酶和pNPPase活性的抑制作用较弱，在该制剂中膜的腔面（细胞外）无法直接接触。这表明SCH 28080在酶的腔面位点抑制两种酶活性。作为一种可质子化的弱碱（pKa = 5.6），预计SCH 28080会以其质子化形式聚集在壁细胞膜的腔面酸性侧。相对于“不可质子化”类似物，SCH 28080的效力在低pH下增加，这与质子化形式的SCH 28080的比例相当。因此，积累的质子化形式是活性抑制物种。在室温下，SCH 28080（50 nM）阻断了（H⁺+K⁺）-ATP酶催化磷酸酶中间体的快速、K⁺刺激的去磷酸化。在4℃时，需要更高浓度的抑制剂，这表明抑制剂在低温下的结合速率较慢。
