Sakuta H, Okamoto K
Department of Pharmacology, National Defense Medical College, Saitama, Japan.
Eur J Pharmacol. 1994 Jul 11;259(3):223-31. doi: 10.1016/0014-2999(94)90648-3.
The effects of imidazoline and imidazolidine derivatives on glibenclamide-sensitive K+ currents induced by the novel K+ channel opener, Y-26763 ((+)-(3S,4R)-4-(N-acetyl-N-benzyloxyamino)-6-cyano-3,4-dihydro-2,2 -dimethyl-2H-1-benzopyran-3-ol), were investigated in voltage-clamped follicle-enclosed Xenopus oocytes. Of 14 imidazoline derivatives and seven imidazolidine derivatives tested, phenotalmine, (-)-cibenzoline, (+)-cibenzoline, alinidine, oxymetazoline, antazoline, midaglizole, xylometazoline, tramazoline and ST91 (2-(2,6-diethylphenylamino)-2-imidazoline hydrochloride) potently suppressed Y-26763-induced K+ currents (IC50 < 80 microM). The compounds which lack an aromatic ring in their structure, 2-methyl-2-imidazole and 2-hydrazino-2-imidazoline, did not affect the K+ currents. Clonidine and idazoxan, which both bind to imidazoline-preferring binding sites with high affinity in various tissues, showed only a small inhibitory effect on Y-26763-induced K+ currents (IC50 780 microM and 955 microM, respectively). The non-imidazoline/non-imidazolidine alpha-adrenoceptor antagonists, WB-4101 (2-(2,6-dimethoxy-phenoxyethyl)-aminomethyl-1,4-benzodioxane hydrochloride), yohimbine and rauwolscine, showed suppressive effects on Y-26763-induced K+ currents (IC50 203 microM, 813 microM and 832 microM, respectively). Octopamine (1 mM), a non-imidazoline/non-imidazolidine alpha-adrenoceptor agonist, was inactive. The results suggest that (1) an aromatic ring or aromatic rings are an essential moiety for imidazoline or imidazolidine derivatives to block glibenclamide-sensitive K+ currents in oocytes, and (2) the K+ current-blocking ability of imidazolines and imidazolidines is related to the alkylation of the benzene ring and the existence of a tertiary amine structure. The K+ current-blocking effects of imidazolines or imidazolidines may not be mediated by alpha-adrenoceptors, at least in follicle-enclosed Xenopus oocytes.
在电压钳制的非洲爪蟾卵泡包被卵母细胞中，研究了咪唑啉和咪唑烷衍生物对新型钾通道开放剂Y - 26763（(+)-(3S,4R)-4-(N - 乙酰 - N - 苄氧基氨基)-6 - 氰基 - 3,4 - 二氢 - 2,2 - 二甲基 - 2H - 1 - 苯并吡喃 - 3 - 醇）诱导的格列本脲敏感钾电流的影响。在所测试的14种咪唑啉衍生物和7种咪唑烷衍生物中，酚妥拉明、(-)-西苯唑啉、(+)-西苯唑啉、阿利尼定、羟甲唑啉、安他唑啉、米哒格列唑、赛洛唑啉、曲马唑啉和ST91（2 - (2,6 - 二乙基苯基氨基)-2 - 咪唑啉盐酸盐）能有效抑制Y - 26763诱导的钾电流（半数抑制浓度<80 μM）。结构中缺乏芳香环的化合物2 - 甲基 - 2 - 咪唑和2 - 肼基 - 2 - 咪唑啉对钾电流无影响。可乐定和伊达唑胺在各种组织中均以高亲和力结合咪唑啉优先结合位点，它们对Y - 26763诱导的钾电流仅表现出较小的抑制作用（半数抑制浓度分别为780 μM和955 μM）。非咪唑啉/非咪唑烷α - 肾上腺素能受体拮抗剂WB - 4101（2 - (2,6 - 二甲氧基苯氧基乙基)-氨基甲基 - 1,4 - 苯并二恶烷盐酸盐）、育亨宾和利血胺对Y - 26763诱导的钾电流有抑制作用（半数抑制浓度分别为203 μM、813 μM和832 μM）。非咪唑啉/非咪唑烷α - 肾上腺素能受体激动剂奥克巴胺（1 mM）无活性。结果表明：(1) 一个或多个芳香环是咪唑啉或咪唑烷衍生物在卵母细胞中阻断格列本脲敏感钾电流的必需部分；(2) 咪唑啉和咪唑烷的钾电流阻断能力与苯环的烷基化和叔胺结构的存在有关。咪唑啉或咪唑烷的钾电流阻断作用可能至少在非洲爪蟾卵泡包被卵母细胞中不是由α - 肾上腺素能受体介导的。
