Cohen M L, Kurz K D, Fuller R W, Calligaro D O
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285.
J Pharm Pharmacol. 1994 Mar;46(3):226-9. doi: 10.1111/j.2042-7158.1994.tb03784.x.
Amesergide is an orally active ergoline amide, 5-HT2-receptor antagonist with a long duration of action. Since a major metabolite of amesergide is 4-hydroxyamesergide, we questioned whether the formation of this metabolite might contribute to the pharmacological activity and long duration of action observed after oral administration of amesergide. 4-Hydroxyamesergide was a potent 5-HT2-receptor antagonist with an affinity equal to or greater than amesergide under in-vitro conditions as measured by blockade of vascular 5-HT2 receptors, and 5-hydroxytryptamine (5-HT)-amplified ADP-induced rabbit platelet aggregation. Furthermore, 4-hydroxyamesergide, like amesergide, inhibited the pressor response to 5-HT after its intravenous administration to rats and was about 3-fold more potent than amesergide in this regard. 4-Hydroxyamesergide was also a potent inhibitor of vascular 5-HT2 receptors after oral administration to rats. After oral administration, 4-hydroxyamesergide had a similar or slightly greater duration of activity than the parent molecule. 4-Hydroxyamesergide, again like amesergide, also blocked central 5-HT2 receptors after its in-vivo administration to rats as measured by its ability to inhibit quipazine-induced increases in serum corticosterone. Thus, the formation of 4-hydroxyamesergide after oral administration of amesergide to animals and man may contribute to the potency and long duration of action of amesergide as a 5-HT2-receptor antagonist.
阿美舍吉德是一种口服活性麦角酰胺，为5-羟色胺2（5-HT2）受体拮抗剂，作用持续时间长。由于阿美舍吉德的主要代谢产物是4-羟基阿美舍吉德，我们质疑该代谢产物的形成是否可能对口服阿美舍吉德后观察到的药理活性和作用持续时间有贡献。在体外条件下，通过阻断血管5-HT2受体以及5-羟色胺（5-HT）增强的ADP诱导的兔血小板聚集测定，4-羟基阿美舍吉德是一种强效5-HT2受体拮抗剂，其亲和力等于或大于阿美舍吉德。此外，与阿美舍吉德一样，4-羟基阿美舍吉德静脉注射给大鼠后可抑制对5-HT的升压反应，在这方面其效力比阿美舍吉德强约3倍。口服给大鼠后，4-羟基阿美舍吉德也是血管5-HT2受体的强效抑制剂。口服后，4-羟基阿美舍吉德的活性持续时间与母体分子相似或略长。同样与阿美舍吉德一样，通过其抑制喹哌嗪诱导的血清皮质酮升高的能力测定，4-羟基阿美舍吉德在体内给大鼠给药后也可阻断中枢5-HT2受体。因此，给动物和人口服阿美舍吉德后形成的4-羟基阿美舍吉德可能有助于阿美舍吉德作为5-HT2受体拮抗剂的效力和作用持续时间。
