Trivedi S, Stetz S L, Potter-Lee L, McConville M, Li J H, Empfield J, Ohnmacht C J, Russell K, Brown F J, Trainor D A
Department of Pharmacology, Zeneca Pharmaceuticals Group, Zeneca Inc., Wilmington, DE 19897, USA.
Pharmacology. 1995 Jun;50(6):388-97. doi: 10.1159/000139308.
Zeneca ZD6169, (S)-N-(4-benzoylphenyl)-3,3,3-trifluoro- 2-hydroxy-2-methylpropionamide, is a novel compound which relaxes urinary bladder smooth muscle in vitro. The effect of ZD6169 and two of its analogs on 86Rb efflux and 3H-P1075 binding in guinea pig bladder strips was investigated to characterize the K-channel opening properties of this compound. ZD6169 concentration dependently increased the rate of 86Rb efflux from guinea pig bladder strips. 86Rb efflux evoked by ZD6169 and its analogs was blocked by glibenclamide (30 muM) but not by charybdotoxin, apamin or alpha-dendrotoxin, suggesting that this compound activates KATP channels in guinea pig bladder. In addition, interaction of ZD6169 with KATP channels was also confirmed in human bladder smooth muscle cells. Specific binding of 3H-P1075, a potent opener of KATP channels, to guinea pig urinary bladder strips was observed. 3H-P1075 binding was inhibited by known KATP openers. ZD6169 inhibited binding of 3H-P1075 to urinary bladder strips like other structurally different KATP openers, e.g. cromakalim and pinacidil. Potencies for inhibition of 3H-P1075 binding by ZD6169 and other potassium channel openers correlate well with potencies for increase in 86Rb efflux and bladder muscle relaxation studies. It is concluded that Zeneca ZD6169 is a potassium channel opener which activates ATP-sensitive K-channels in guinea pig urinary bladder strips as well as in human bladder cells. Furthermore, binding studies suggest that the effects of ZD6169 and its analogs are mediated by binding to the site labeled by 3H-P1075 in guinea pig bladder strips.
捷利康公司的ZD6169，即(S)-N-(4-苯甲酰基苯基)-3,3,3-三氟-2-羟基-2-甲基丙酰胺，是一种新型化合物，它在体外可使膀胱平滑肌舒张。研究了ZD6169及其两种类似物对豚鼠膀胱条带中86Rb外流和3H-P1075结合的影响，以表征该化合物的钾通道开放特性。ZD6169浓度依赖性地增加了豚鼠膀胱条带中86Rb的外流速率。ZD6169及其类似物诱发的86Rb外流被格列本脲（30μM）阻断，但未被蝎毒素、蜂毒明肽或α-树眼镜蛇毒素阻断，这表明该化合物可激活豚鼠膀胱中的ATP敏感性钾通道（KATP通道）。此外，在人膀胱平滑肌细胞中也证实了ZD6169与KATP通道的相互作用。观察到3H-P1075（一种有效的KATP通道开放剂）与豚鼠膀胱条带的特异性结合。已知的KATP开放剂可抑制3H-P1075的结合。ZD6169与其他结构不同的KATP开放剂（如克罗卡林和平尼地尔）一样，可抑制3H-P1075与膀胱条带结合。ZD6169和其他钾通道开放剂对3H-P1075结合的抑制效力与86Rb外流增加和膀胱肌肉舒张研究中的效力密切相关。得出的结论是，捷利康公司的ZD6169是一种钾通道开放剂，它可激活豚鼠膀胱条带以及人膀胱细胞中的ATP敏感性钾通道。此外，结合研究表明，ZD6169及其类似物的作用是通过与豚鼠膀胱条带中被3H-P1075标记的位点结合来介导的。
