Beyerle R, Bohn H, Schönafinger K, Martorana P A, Bender H
Arzneimittelforschung. 1985;35(1):93-102.
The syntheses of new 2-aryl-2-imidazolinyl-acetic acids and esters are reported together with pharmacological results concerning structure-activity relationship. In contrast to the already known but inactive N(1)-alkylated derivatives of 2-arylamino-2-imidazolines the new compounds with an aryl acetic acid substitution in N(1) position of the imidazoline nucleus show the bradykardic activity of the exocyclic alkylated clonidine derivatives such as alinidine. The majority of these new substances reduce blood pressure and heart rate in anesthetized rats significantly with a long duration of action. 2-[2-(2,6-Dichloro-phenylamine)-2-imidazoline-1-yl]-2-(2-thienyl)- acetic acid 8a is the most potent compound. Blood pressure is lowered by 30-40 mmHg and heart rate by 175 beats/min with a duration of action greater than 60 min. The effect is weakened if the thienyl radical is replaced by other heterocycles or if the 2,6-dichlorphenyl group is replaced by a hydrogen atom. The variation of the substituents in the phenyl nucleus shows that the 2,6-dichlorphenyl structure is the optimum substitution pattern, as in the case of clonidine. In the series comprising the 2-[2-(2,6-dichlorphenylamino)-2-imidazoline-1-yl]-2-phenyl acetic acids (8j-8n) the incorporation of different substituents into the phenyl nucleus in the 2-position results in derivates of different activity. The esters 9a-9c show a faster onset of action as compared to the corresponding carboxylic acid 8a. The most interesting effect of compound 8a in normotensive conscious dogs is a strong and long-lasting decrease in heart rate accompanied by a moderate LVP dp/dtmax decrease, weak lowering of blood pressure and slight increase in LVEDP. After blocking beta-receptors by atenolol the compound 8a still reduces heart rate. Results in ganglion-blocked and pithed rats indicate a presynaptic and postsynaptic alpha 2-agonistic effect. A decrease in sympathetic tone as well as an increase in vagal activity in conscious dogs are considered as possible causes for bradycardic activity. Unlike alinidine, however, compound 8a does not affect directly sinus node function. The bradycardic effect of compound 8a which results in a decrease in oxygen consumption is supposed to be the cause of the reduction of infarct size in anesthetized dogs by 28%.
报道了新型2-芳基-2-咪唑啉基乙酸及其酯的合成以及有关构效关系的药理学结果。与已知的无活性的2-芳基氨基-2-咪唑啉的N(1)-烷基化衍生物不同，咪唑啉核N(1)位被芳基乙酸取代的新型化合物具有环外烷基化可乐定衍生物（如阿利尼定）的减慢心率活性。这些新物质中的大多数能显著降低麻醉大鼠的血压和心率，且作用持续时间长。2-[2-(2,6-二氯苯胺)-2-咪唑啉-1-基]-2-(2-噻吩基)乙酸8a是最有效的化合物。血压降低30 - 40 mmHg，心率降低175次/分钟，作用持续时间超过60分钟。如果噻吩基被其他杂环取代，或者2,6-二氯苯基被氢原子取代，效果会减弱。苯环上取代基的变化表明，2,6-二氯苯基结构是最佳取代模式，与可乐定的情况相同。在由2-[2-(2,6-二氯苯胺)-2-咪唑啉-1-基]-2-苯基乙酸（8j - 8n）组成的系列中，在2-位苯环上引入不同取代基会导致活性不同的衍生物。酯9a - 9c与相应的羧酸8a相比起效更快。化合物8a对正常血压清醒犬最有趣的作用是心率强烈且持久地降低，同时左心室压力最大上升速率适度降低、血压轻度下降以及左心室舒张末期压力略有升高。用阿替洛尔阻断β受体后，化合物8a仍能降低心率。在神经节阻断和脊髓切断的大鼠中的结果表明其具有突触前和突触后α2激动作用。清醒犬交感神经张力降低以及迷走神经活动增加被认为是心率减慢活性的可能原因。然而，与阿利尼定不同，化合物8a不直接影响窦房结功能。化合物8a的心率减慢作用导致耗氧量降低，这被认为是麻醉犬梗死面积减少28%的原因。
