Turconi M, Nicola M, Quintero M G, Maiocchi L, Micheletti R, Giraldo E, Donetti A
Department of Medicinal Chemistry, Istituto De Angeli, Milan, Italy.
J Med Chem. 1990 Aug;33(8):2101-8. doi: 10.1021/jm00170a009.
A series of 2,3-dihydro-2-oxo-1H-benzimidazole-1-carboxylic acid esters and amides containing a basic azacyclo- or azabicycloalkyl moiety has been synthesized and evaluated for 5-HT3 antagonistic activity in a radioligand binding assay ([3H]ICS 205930) and in the 5-HT-induced von Bezold-Jarisch reflex in the rat. It was found that endo-substituted azabicycloalkyl derivatives (e.g. 7a, 12a, 12b) were much more active than the corresponding exo analogues (e.g. 7b, 12h, 12i) or azacycloalkyl compounds. Amidic derivatives 12a, 12b, 12c, 12e, 13b, and 13c proved to be about 10 times more active than the corresponding ester derivatives 7a, 11a, 7c, 7d, 8a, and 8b. In particular, compound 12a (DA 6215) showed a Ki = 3.8 nM in the binding test and an ED50 = 1 nM/kg iv in the von Bezold-Jarisch reflex assay, an activity comparable to that of the reference compound 2 (ICS 205930, Ki = 2 nM, ED50 = 2.1 nM/kg). IR spectroscopy studies in the solid state and in CHCl3 solution revealed the existence of an intramolecular hydrogen bond in 13b, taken as a model compound for this class of substances. A molecular modeling study showed that 12a, in its internal hydrogen-bound conformation, well matches a recently proposed pharmacophoric model for 5-HT3 antagonist activity.
已经合成了一系列含有碱性氮杂环或氮杂双环烷基部分的2,3 - 二氢 - 2 - 氧代 - 1H - 苯并咪唑 - 1 - 羧酸酯和酰胺，并在放射性配体结合试验（[3H] ICS 205930）以及大鼠5 - 羟色胺诱导的贝佐尔德 - 雅里什反射中评估了它们的5 - HT3拮抗活性。发现内型取代的氮杂双环烷基衍生物（例如7a、12a、12b）比相应的外型类似物（例如7b、12h、12i）或氮杂环烷基化合物活性高得多。酰胺衍生物12a、12b、12c、12e、13b和13c被证明比相应的酯衍生物7a、11a、7c、7d、8a和8b活性高约10倍。特别地，化合物12a（DA 6215）在结合试验中显示Ki = 3.8 nM，在贝佐尔德 - 雅里什反射试验中静脉注射的ED50 = 1 nM/kg，其活性与参考化合物2（ICS 205930，Ki = 2 nM，ED50 = 2.1 nM/kg）相当。在固态和CHCl3溶液中的红外光谱研究表明，作为这类物质的模型化合物的13b中存在分子内氢键。分子建模研究表明，12a在其内部氢键结合构象中与最近提出的5 - HT3拮抗剂活性药效团模型非常匹配。
