IMIDAZO[1,2-B]PYRIDAZINES .6. SYNTHESES AND CENTRAL NERVOUS-SYSTEM ACTIVITIES OF SOME 6-(ALKOXY-PHENOXY AND METHYLTHIO-PHENOXY AND METHOXYBENZYLTHIO)-3-METHOXY-2-PHENYL(SUBSTITUTED PHENYL AND PYRIDINYL)IMIDAZO[1,2-B]PYRIDAZINES
IMIDAZO[1,2-B]PYRIDAZINES .6. SYNTHESES AND CENTRAL NERVOUS-SYSTEM ACTIVITIES OF SOME 6-(ALKOXY-PHENOXY AND METHYLTHIO-PHENOXY AND METHOXYBENZYLTHIO)-3-METHOXY-2-PHENYL(SUBSTITUTED PHENYL AND PYRIDINYL)IMIDAZO[1,2-B]PYRIDAZINES
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DOI：
10.1071/ch9891735
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发表时间：
1989-01-01
影响因子：
1.1
通讯作者：
NGU, MML
中科院分区：
文献类型：
--
作者：
BARLIN, GB;DAVIES, LP;NGU, MML
制备了一系列6-（烷氧基-和甲硫基-苯氧基）-2-苯基（取代的苯基和吡啶基）咪唑并[1，2-B]哒嗪和3-甲氧基-6-（甲氧基苄硫基）-2-苯基（取代的苯基和吡啶基）咪唑并[1，2-B]哒嗪，随后测试了它们抑制GABA刺激的~ 3 H-地西泮与大鼠脑质膜结合的能力。6-（烷氧基-和甲硫基-苯氧基）和6-（甲氧基苄硫基）化合物在置换研究中分别比母体6-苯氧基或6-苄硫基化合物有效得多。3-甲氧基-6-（2“-甲氧基苯氧基）-2-苯基咪唑并[1，2-B]哒嗪（GBLD-167，IC 50 70 nM）比其3-甲氧基-6-苯氧基类似物有效16倍（GBLD-163，IC 50 1120 nM）和3-甲氧基-6-（4-甲氧基苯基）-2-（4-甲氧基苯基）-3-（4-甲氧基苯基）-2-（4-甲氧基苯基）-3-（（2 ''-甲氧基苄硫基）-2-苯基化合物（GBLD-214，IC 50 9 nM）的活性是其6-苄硫基-3-甲氧基类似物（GBLD-137，IC 50 22 nM）的2.5倍。6-苯氧基系列中最活跃的成员是2-（4“-氟苯基）-3-甲氧基-6-（2”-甲氧基苯氧基）化合物（GBLD-255，IC 50 30 nM），在6-苄硫基系列中，2-（4“-氟苯基、3”-氨基苯基和吡啶-3“-基）-3-甲氧基-6-（3”-甲氧基苄硫基）化合物（GBLD-233、301和296）的IC 50均为5 nM。这两个密切相关的系列化合物的结果的Hansch型分析表明，2-（帕拉取代苯基）衍生物中的给电子取代基有利于结合，但庞大的取代基阻碍这种效果。
Series of 6-(alkoxy- and methylthio-phenoxy)-2-phenyl(substituted phenyl and pyridinyl)imidazo[1,2-b]pyridazines and 3-methoxy-6-(methoxybenzylthio)-2-phenyl(substituted phenyl and pyridinyl)imidazo[1,2-b]pyridazines have been prepared and subsequently tested for their ability to inhibit GABA-stimulated 3H-diazepam binding to rat brain plasma membranes. The 6-(alkoxy- and methylthio-phenoxy) and 6-(methoxybenzylthio) compounds were much more effective in the displacement studies than the parent 6-phenoxy or 6-benzylthio compounds respectively. 3-Methoxy-6-(2''-methoxyphenoxy)-2-phenylimidazo[1,2-b]pyridazine (GBLD-167, IC50 70 nM) was 16 times more effective than its 3-methoxy-6-phenoxy analogue (GBLD-163, IC50 1120 nM) and the 3-methoxy-6-(2''-methoxybenzylthio)-2-phenyl compound (GBLD-214, IC50 9 nM) was two and a half times more active than its 6-benzylthio-3-methoxy analogue (GBLD-137, IC50 22 nM). The most active member of the 6-phenoxy series was the 2-(4''-fluorophenyl)-3-methoxy-6-(2"-methoxyphenoxy) compound (GBLD-255, IC50 30 nM) and, within the 6-benzylthio series, the 2-(4''-fluorophenyl, 3''-aminophenyl, and pyridin-3''-yl)-3-methoxy-6-(3"-methoxybenzylthio) compounds (GBLD-233, 301 and 296) all gave IC50 5 nM. A Hansch-type analysis of the results for these two closely related series of compounds indicates that electron-donating substituents in 2-(para substituted phenyl) derivatives favour binding, but bulky substituents hinder this effect.