Dini S, Caselli G F, Basilico C, Lavezzo A, Giani R
Research and Development Department, DOMPE Farmaceutici S.p.A., Milan, Italy.
Agents Actions. 1990 Apr;30(1-2):174-7. doi: 10.1007/BF01969030.
A new series of 2-dialkylamino-alkylthio(oxy)-1-substituted benzimidazoles synthesized in our laboratories was found to have promising antihistaminic activity. The results of pharmacological screening ("in vitro": radioreceptor binding and isolated organs; "in vivo": protection against mortality induced by histamine or by compound 48/80, passive cutaneous anaphylaxis, and prolongation of barbiturate-induced sleeping-time) gave clear-cut structure-activity relationships. This series of products has a general selectivity towards H1 receptors, weak antiallergic properties and negligible central effects. DF 10967 (1-ethoxyethyl-2-dimethyl-aminoethylthiobenzimidazole) was the most interesting compound, being very potent both "in vitro" (Ki = 3.2 +/- 0.8 nM) and "in vivo" (ID50 11 micrograms/kg, i.p. and 8 micrograms/kg, i.p. against histamine- and 48/80-induced mortality), with no central effects. The last finding is probably due to poor penetration into the brain (as confirmed by "in vivo" binding test with [3H]-mepyramine) and to lack of interaction with other central receptors.
我们实验室合成的一系列新的2-二烷基氨基-烷硫基（氧基）-1-取代苯并咪唑被发现具有良好的抗组胺活性。药理筛选结果（“体外”：放射受体结合和离体器官实验；“体内”：对组胺或48/80诱导的死亡的保护作用、被动皮肤过敏反应以及巴比妥酸盐诱导睡眠时间的延长）给出了明确的构效关系。该系列产品对H1受体具有一般选择性，抗过敏特性较弱且中枢作用可忽略不计。DF 10967（1-乙氧基乙基-2-二甲基氨基乙基硫代苯并咪唑）是最引人关注的化合物，在“体外”（Ki = 3.2 +/- 0.8 nM）和“体内”（腹腔注射时，对组胺和48/80诱导的死亡的ID50分别为11微克/千克和8微克/千克）均具有很强的活性，且无中枢作用。最后这一发现可能是由于其难以穿透血脑屏障（通过[3H]-美吡拉敏的“体内”结合试验证实）以及与其他中枢受体缺乏相互作用。
