AT-1015, a novel serotonin (5-HT)(2) receptor antagonist, blocks vascular and platelet 5-HT2A receptors and prevents the laurate-induced peripheral vascular lesion in rats

The serotonin (5-HT2A) antagonistic activities and the protective effect on laurate-induced peripheral vascular lesions of AT-1015, a novel 5-HT2 rece ptor antagonist, were investigated. In platelet aggregation, AT-1015 select ively inhibited in vitro 5-HT2A receptor-mediated aggregation, and the acti vity was almost equivalent to that of ketanserin (5-HT2A/2C receptor antago nist) and 100 times more potent than sarpogrelate (5-HT2A receptor antagoni st). AT-1015 also inhibited 5-HT2A receptor-mediated aggregation by oral ad ministration in rat, and the dose required for inhibition was equivalent to ketanserin. In a 5-HT-induced vasoconstriction study in rat, AT-1015 sligh tly reduced maximal contraction and caused a rightward shift of the concent ration-response curve (pK(B) value, 9.5), which was unlike competitive inhi bitors such as ketanserin and sarpogrelate (pA(2) value, 9.3 and 8.7, respe ctively). Moreover, the ex vivo inhibitory activity significantly remained after oral administration (1 mg/kg). In the rat peripheral vascular lesion model, AT-1015 (1 mg/kg, p.o.) effectively prevented progression of periphe ral lesions, and it was more potent compared with ketanserin, sarpogrelate, and cilostazol. These results suggest that AT-1015 is a potent 5-HT2A rece ptor antagonist, and its insurmountable antagonism may be relevant to its t herapeutic potential in peripheral vascular disease.