Hadley M S, King F D, McRitchie B, Turner D H, Watts E A
J Med Chem. 1985 Dec;28(12):1843-7. doi: 10.1021/jm00150a015.
The gastric prokinetic action of metoclopramide may not be primarily due to its dopamine antagonist activity. The present aim was to obtain a selective gastric prokinetic agent lacking dopamine antagonist activity by conformationally restricting the side chain of metoclopramide. In a series of quinolizidinylbenzamides, only compounds with the benzamide moiety at position 2 of the quinolizidine ring retain gastric activity. Of these 2-substituted compounds, the 2 alpha, 9a alpha isomer has potent selective gastric prokinetic activity with only weak dopamine antagonist properties. Spectroscopic data show that the quinolizidine ring preferentially adopts a trans chair-chair conformation with an axial benzamide moiety. However, energy calculations indicate that, at nondopaminergic receptors controlling gastric motility, an alternative cis chair-chair conformation with an equatorial benzamide moiety cannot be ruled out.
甲氧氯普胺的促胃动力作用可能并非主要归因于其多巴胺拮抗活性。当前的目标是通过对甲氧氯普胺侧链进行构象限制来获得一种缺乏多巴胺拮抗活性的选择性促胃动力剂。在一系列喹诺里西丁基苯甲酰胺中，只有喹诺里西丁环2位带有苯甲酰胺部分的化合物保留胃活性。在这些2-取代化合物中，2α, 9aα异构体具有强效的选择性促胃动力活性，而多巴胺拮抗特性较弱。光谱数据表明，喹诺里西丁环优先采取反式椅-椅构象，其中苯甲酰胺部分为轴向。然而，能量计算表明，在控制胃动力的非多巴胺能受体处，不能排除具有赤道苯甲酰胺部分的另一种顺式椅-椅构象。
