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

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Abstract

Serotonin (5-HT) and adrenaline acting at platelet 5-HT2A-serotoninergic and α2-adrenergic receptors are involved in platelet aggregation. We have evaluated the antagonistic potency at 5-HT2A, α2A–, and α2B-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 α2-adrenoceptors, with around 2–7 times stronger antagonistic effect at α2B subtype than α2A 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 α2-adrenergic receptors is effective in preventing aggregation and could constitute alternative antiplatelet therapy.

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