Anti-aggregation effect of aroxyalkyl derivatives of 2-methoxyphenylpiperazine is due to their 5-HT2A and α2-adrenoceptor antagonistic properties. A comparison with ketanserin, sarpogrelate, prazosin, yohimbine and ARC239

Serotonin (5-HT) and adrenaline acting at platelet 5-HT2A-serotoninergic and alpha(2)-adrenergic receptors are involved in platelet aggregation. We have evaluated the antagonistic potency at 5-HT2A, alpha(2A)-, and alpha(2B)-adrenoceptors as well as an anti-aggregation effect of aroxyalkyl derivatives of 2-methoxyphenylpiperazine and compared them with ketanserin, sarpogrelate, prazosin, yohimbine and ARC239 (2-[2-[4-(o-methoxyphenyl)piperazin-1-yl]-ethyl]-4,4-dimethyl-1,3-(2H, 4H)-isoquinolindione). Functional bioassays at cells expressing human receptors, revealed studied compounds to be moderate antagonists of 5-HT2A and alpha(2)-adrenoceptors, with around 2-7 times stronger antagonistic effect at alpha(2B) subtype than alpha(2A) subtype. Further, studied compounds inhibited 5-HT2A-mediated contraction in isolated rat aortic rings and 5-HT vasopressor response in rat in vivo. Studied compounds inhibited collagen stimulated whole rat blood aggregation with compound MH-77 (1-[(2,3-dimethylphenoxy)propyl]-4-(2-methoxyphenyl)piperazine hydrochloride) being more potent than sarpogrelate or yohimbine. They also inhibited 5-HT/adrenaline-, amplified ADP- or collagen-induced platelet aggregation. Simultaneous, moderate blockade of 5-HT2A serotonin and alpha(2)-adrenergic receptors is effective in preventing aggregation and could constitute alternative antiplatelet therapy.