Comparative 5-HT2-receptor antagonist activity of amesergide and its active metabolite 4-hydroxyamesergide in rats and rabbits.
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.
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana 46285.
M L
ML
Cohen
K D
KD
Kurz
R W
RW
Fuller
D O
DO
Calligaro
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D003345:Corticosterone / Q000097:blood; D004873:Ergolines / Q000494:pharmacology*; D066298:In Vitro Techniques; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D010974:Platelet Aggregation / Q000187:drug effects; D011814:Quipazine / Q000037:antagonists & inhibitors / Q000494:pharmacology; D011817:Rabbits; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D011956:Receptors, Cell Surface / Q000187:drug effects; D012702:Serotonin Antagonists / Q000494:pharmacology*
D004873:Ergolines; D011956:Receptors, Cell Surface; D012702:Serotonin Antagonists; C088215:4-hydroxyamesergide; D011814:Quipazine; D000244:Adenosine Diphosphate; C066736:amesergide; D003345:Corticosterone