Li J H, Yasay G D, Zografos P, Kau S T, Ohnmacht C J, Russell K, Empfield J R, Brown F J, Trainor D A, Bonev A D
Department of Pharmacology, Zeneca Inc., Wilmington, Del 19897, USA.
Pharmacology. 1995 Jun;51(1):33-42. doi: 10.1159/000139314.
The potassium (K+) channel opening activity of Zeneca ZD6169 and one of its pyridylsulfonyl analogs from the anilide tertiary carbinol series was ascertained. Their mechanoinhibitory effects on the myogenic activity of the guinea pig bladder detrusor muscle were measured in a set of functional assays. Elevating the K+ concentration in the tissue bath from 15 to 80 mmol/l increased the IC50 value of ZD6169 from 1.61 +/- 0.22 223 +/- 37 mumol/l. This result suggests that ZD6169 may act as a K+ channel opener. Similar to the prototypic ATP-sensitive K+ (KATP) channel opener cromakalim, the K+ channel openers from the anilide tertiary carbinol series displayed stereoselective mechanoinhibitory activity only in the test protocol in which the detrusor was stimulated with 15 mmol/l KCl. Being the active enantiomer, ZD6169 has an activity more than 30-fold higher than the less active enantiomer. ZD6169 at 10 mumol/l hyperpolarized the guinea pig detrusor membrane potential by 6.1 +/- 1.2 mV and increased the whole cell KATP current in isolated guinea pig smooth muscle cells by 34.9 +/- 7.9 pA. This is comparable to the increase of 26.8 +/- 5.0 pA obtained with 10 mumol/l of lemakalim, the active enantiomer of cromakalim. The K+ channel opening activity of ZD6169 and the pyridylsulfonyl analog was competitively antagonized by the KATP channel blocker glibenclamide in the guinea pig detrusor with a pA2 value of 7.2. This activity, however, was unaffected by blockers of small and large conductance Ca-dependent K+ channels, such as apamin and charybdotoxin, respectively. The present study showed that Zeneca ZD6169 and its analog from the anilide tertiary carbinol series are K+ channel openers that activate KATP channels in vitro to relax bladder detrusors.
测定了阿斯利康公司的ZD6169及其苯胺叔丁醇系列中的一种吡啶磺酰类似物的钾（K+）通道开放活性。在一组功能试验中测量了它们对豚鼠膀胱逼尿肌肌源性活动的机械抑制作用。将组织浴中的K+浓度从15mmol/L提高到80mmol/L，ZD6169的IC50值从1.61±0.22μmol/L增加到223±37μmol/L。这一结果表明ZD6169可能作为一种K+通道开放剂发挥作用。与原型ATP敏感性钾（KATP）通道开放剂克罗卡林相似，苯胺叔丁醇系列的K+通道开放剂仅在使用15mmol/L KCl刺激逼尿肌的试验方案中表现出立体选择性机械抑制活性。作为活性对映体，ZD6169的活性比活性较低的对映体高30多倍。10μmol/L的ZD6169使豚鼠逼尿肌膜电位超极化6.1±1.2mV，并使分离的豚鼠平滑肌细胞中的全细胞KATP电流增加34.9±7.9pA。这与用10μmol/L的克罗卡林活性对映体雷马卡林获得的26.8±5.0pA的增加相当。ZD6169和吡啶磺酰类似物的K+通道开放活性在豚鼠逼尿肌中被KATP通道阻滞剂格列本脲竞争性拮抗，pA2值为7.2。然而，这种活性不受小电导和大电导钙依赖性钾通道阻滞剂的影响，如蜂毒明肽和大蝎毒素。本研究表明，阿斯利康公司的ZD6169及其苯胺叔丁醇系列类似物是K+通道开放剂，可在体外激活KATP通道以舒张膀胱逼尿肌。
