Effect of 5-HT2 receptor antagonist ergolines and their desisopropyl metabolites on rabbit platelet aggregation in vitro and ex vivo

Amesergide and LY215840 are potent and long-lasting 5-HT₂ receptor antagonists after oral administration to animals. In animals, these ergolines are metabolized to their desisopropyl ergoline congeners which have lower affinity (40–60 nM) at 5-HT₂ receptors in the rat relative to higher 5-HT₂ receptor affinity (2–3 nM) at the cloned human 5-HT₂ receptor. Because amesergide and LY215840 are effective in rabbit models of thrombosis, we asked whether their efficacy in the rabbit was related in part to the activity of both the parent and desisopropyl metabolites at rabbit platelet 5-HT₂ receptors. Platelet aggregation responses were first optimized to ADP and the combination of ADP and serotonin with regard to platelet number (300,000 platelets/μl of plasma) and time (70 to 140 min after platelet harvest). In ex vivo studies, both amesergide and LY215840 (3.0 mg/kg p.o.) showed similar and marked antagonism of rabbit platelet 5-HT₂ receptors at 1 and 24 h after their oral administration to rabbits. Furthermore, the desisopropyl ergoline metabolites of both amesergide and LY215840 inhibited serotonin-amplified platelet aggregation responses in vitro as did amesergide and LY215840. Thus, these studies add support to the hypothesis that the desisopropyl metabolites of amesergide and LY215840 may contribute to the oral antithrombotic efficacy of the parent molecules in rabbits.