Gedda Karin, Briving Carin, Svensson Karin, Maxvall Ingela, Andersson Kjell
AstraZeneca R&D, Mölndal S-431 83, Sweden.
Biochem Pharmacol. 2007 Jan 15;73(2):198-205. doi: 10.1016/j.bcp.2006.09.020. Epub 2006 Sep 24.
AZD0865 is a member of a drug class that inhibits gastric H(+),K(+)-ATPase by K(+)-competitive binding. The objective of these experiments was to characterize the mechanism of action, selectivity and inhibitory potency of AZD0865 in vitro. In porcine ion-leaky vesicles at pH 7.4, AZD0865 concentration-dependently inhibited K(+)-stimulated H(+),K(+)-ATPase activity (IC(50) 1.0+/-0.2 microM) but was more potent at pH 6.4 (IC(50) 0.13+/-0.01 microM). The IC(50) values for a permanent cation analogue, AR-H070091, were 11+/-1.2 microM at pH 7.4 and 16+/-1.8 microM at pH 6.4. These results suggest that the protonated form of AZD0865 inhibits H(+),K(+)-ATPase. In ion-tight vesicles, AZD0865 inhibited H(+),K(+)-ATPase more potently (IC(50) 6.9+/-0.4 nM) than in ion-leaky vesicles, suggesting a luminal site of action. AZD0865 inhibited acid formation in histamine- or dibutyryl-cAMP-stimulated rabbit gastric glands (IC(50) 0.28+/-0.01 and 0.26+/-0.003 microM, respectively). In ion-leaky vesicles at pH 7.4, AZD0865 (3 microM) immediately inhibited H(+),K(+)-ATPase activity by 88+/-1%. Immediately after a 10-fold dilution H(+),K(+)-ATPase inhibition was 41%, indicating reversible binding of AZD0865 to gastric H(+),K(+)-ATPase. In contrast to omeprazole, AZD0865 inhibited H(+),K(+)-ATPase activity in a K(+)-competitive manner (K(i) 46+/-3 nM). AZD0865 inhibited the process of cation occlusion concentration-dependently (IC(50) 1.7+/-0.06 microM). At 100 microM, AZD0865 reduced porcine renal Na(+),K(+)-ATPase activity by 9+/-2%, demonstrating a high selectivity for H(+),K(+)-ATPase. Thus, AZD0865 potently, K(+)-competitively, and selectively inhibits gastric H(+),K(+)-ATPase activity and acid formation in vitro, with a fast onset of effect.
AZD0865是一类通过钾离子竞争性结合来抑制胃H⁺,K⁺-ATP酶的药物成员。这些实验的目的是在体外表征AZD0865的作用机制、选择性和抑制效力。在pH 7.4的猪离子泄漏囊泡中，AZD0865浓度依赖性地抑制钾离子刺激的H⁺,K⁺-ATP酶活性（半数抑制浓度[IC₅₀]为1.0±0.2微摩尔/升），但在pH 6.4时更有效（IC₅₀为0.13±0.01微摩尔/升）。一种永久性阳离子类似物AR-H070091在pH 7.4时的IC₅₀值为11±1.2微摩尔/升，在pH 6.4时为16±1.8微摩尔/升。这些结果表明AZD0865的质子化形式抑制H⁺,K⁺-ATP酶。在离子紧密囊泡中，AZD0865比在离子泄漏囊泡中更有效地抑制H⁺,K⁺-ATP酶（IC₅₀为6.9±0.4纳摩尔/升），表明其作用位点在管腔。AZD0865抑制组胺或二丁酰环磷腺苷刺激的兔胃腺中的酸形成（IC₅₀分别为0.28±0.01和0.26±
