Yoshida N, Omoya H, Kato S, Ito T
Exploratory Research Laboratories, Dainippon Pharmaceutical Co., Ltd., Suita/Osaka, Japan.
Arzneimittelforschung. 1993 Oct;43(10):1078-83.
The pharmacological effects of the metabolites M1 and M2 of mosapride citrate ((+/-)-4-amino-5-chloro-2-ethoxy-N-[[4-(4-fluorobenzyl)-2-morpholi nyl] methyl]benzamide citrate, AS-4370, CAS 112885-42-4), a gastroprokinetic agent with serotonin 5-HT4 receptor agonist property, were compared with those of mosapride. In isolated guinea-pig ileum treated with phenoxybenzamine, the metabolites M1 and M2 enhanced electrically-evoked contractions with EC50 values of 1.2 x 10(-7) mol/l and 1.0 x 10(-6) mol/l, respectively. The metabolite M1 was twice less potent than that of mosapride. When administered intravenously, the metabolite M1 enhanced gastric emptying of a semisolid meal in mice and rats; the potency was 3 times less than that of mosapride in mice and almost equal to that of mosapride in rats. When administered orally, the metabolite M1 enhanced gastric emptying of a semisolid meal in mice and rats, and also enhanced gastric emptying of a resin pellet meal in rats. The potency of metabolite M1 was 10 times less than that of mosapride in rats, although it was equal to that of mosapride in mice. In these experiments, the metabolite M2 was far less active. In addition to these gastroprokinetic properties, the metabolite M1 possessed a potent 5-HT3 receptor antagonist property. The metabolite M1 antagonized the 2-methyl-5-HT-induced bradycardia in anesthetized rats with an ED50 value of 10.5 micrograms/kg, i.v., and inhibited the cisplatin-induced emesis in ferrets with a potency approximately 25 times that of mosapride. These results suggest that the metabolites M1 and M2 of mosapride do not play a crucial role in the gastroprokinetic effect of mosapride.(ABSTRACT TRUNCATED AT 250 WORDS)
枸橼酸莫沙必利（(+/-)-4-氨基-5-氯-2-乙氧基-N-[[4-(4-氟苄基)-2-吗啉基]甲基]苯甲酰胺枸橼酸盐，AS-4370，CAS 112885-42-4）是一种具有5-羟色胺5-HT4受体激动剂特性的促胃肠动力药，对其代谢产物M1和M2的药理作用与莫沙必利进行了比较。在用酚苄明处理的离体豚鼠回肠中，代谢产物M1和M2增强电诱发收缩，其半数有效浓度（EC50）值分别为1.2×10⁻⁷mol/L和1.0×10⁻⁶mol/L。代谢产物M1的效力比莫沙必利低两倍。静脉给药时，代谢产物M1增强小鼠和大鼠半固体食物的胃排空；在小鼠中效力比莫沙必利低3倍，在大鼠中几乎与莫沙必利相当。口服给药时，代谢产物M1增强小鼠和大鼠半固体食物的胃排空，也增强大鼠树脂小球食物的胃排空。在大鼠中代谢产物M1的效力比莫沙必利低10倍，尽管在小鼠中与莫沙必利相当。在这些实验中，代谢产物M2的活性远较低。除了这些促胃肠动力特性外，代谢产物M1还具有强效的5-HT3受体拮抗特性。代谢产物M1拮抗麻醉大鼠中2-甲基-5-HT诱导的心动过缓，静脉注射半数有效剂量（ED50）值为10.5微克/千克，并抑制雪貂中顺铂诱导的呕吐，效力约为莫沙必利的25倍。这些结果表明，莫沙必利的代谢产物M1和M2在莫沙必利的促胃肠动力作用中不发挥关键作用。（摘要截短至250字）
