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 receptor antagonist, were investigated. In platelet aggregation, AT-1015 selectively inhibited in vitro 5-HT2A receptor-mediated aggregation, and the activity was almost equivalent to that of ketanserin (5-HT2A/2C receptor antagonist) and 100 times more potent than sarpogrelate (5-HT2A receptor antagonist). AT-1015 also inhibited 5-HT2A receptor-mediated aggregation by oral administration in rat, and the dose required for inhibition was equivalent to ketanserin. In a 5-HT-induced vasoconstriction study in rat, AT-1015 slightly reduced maximal contraction and caused a rightward shift of the concentration-response curve (pK(B) value, 9.5), which was unlike competitive inhibitors such as ketanserin and sarpogrelate (pA(2) value, 9.3 and 8.7, respectively). 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 peripheral lesions, and it was more potent compared with ketanserin, sarpogrelate, and cilostazol. These results suggest that AT-1015 is a potent 5-HT2A receptor antagonist, and its insurmountable antagonism may be relevant to its therapeutic potential in peripheral vascular disease.