The antithrombotic activity of N-[2-(4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidino)ethyl]-1-formyl-4-piperidinecarboxamide monohydrochloride monohydrate (
AT-1015; a 5-HT(2A) receptor antagonist) was studied in a photochemically induced arterial
thrombosis (PIT) model in the rat femoral artery, and in the tail transection bleeding time test.
Ticlopidine (an
antiplatelet agent) and
sarpogrelate (a selective 5-HT(2A) receptor antagonist) were studied as reference compounds. Pretreatment with
AT-1015 (1 mg/kg, p.o.) significantly prolonged the time required to occlusion of the artery with
thrombus, and the effect (3 mg/kg, p.o.) persisted for 24 h with significant inhibition of 5-HT-induced vascular contraction.
Ticlopidine and
sarpogrelate also significantly prolonged the time to occlusion at 100 mg/kg, p.o.
Sarpogrelate (300 mg/kg, p.o.) showed the similar antithrombotic efficacy to
AT-1015 (3 mg/kg, p.o.), while the effect disappeared within 6 h. No significant bleeding time prolongation was observed
at 10 mg/kg of
AT-1015, which is 10 times higher than the antithrombotic effective dose; whereas
ticlopidine significantly prolonged bleeding time at the same dose as the antithrombotic effective dose. These results suggested that
AT-1015 is a potent and long-acting oral
antithrombotic agent in this model, which may be elucidated by its potent and long-acting inhibition of vasoconstriction through
5-HT(2A) receptor.