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

Abstract

Serotonin (5-HT) and adrenaline acting at platelet 5-HT_2A-serotoninergic and α₂-adrenergic receptors are involved in platelet aggregation. We have evaluated the antagonistic potency at 5-HT_2A, α_2A-, and α_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-HT_2A and α₂-adrenoceptors, with around 2-7 times stronger antagonistic effect at α_2B subtype than α_2A subtype. Further, studied compounds inhibited 5-HT_2A-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-HT_2A serotonin and α₂-adrenergic receptors is effective in preventing aggregation and could constitute alternative antiplatelet therapy.

Keywords: (±)-Epinephrine hydrochloride (PubChem CID: 9489); 5-HT(2A); ARC239 (PubChem CID: 609483); Aggregation; Ketanserin tartrate (PubChem CID: 16219944); Sarpogrelate hydrochloride (PubChem CID: 444005); Serotonin; Serotonin hydrochloride (PubChem CID: 160436); Yohimbine hydrochloride (PubChem CID: 6169); α(2A)-adrenoceptors; α(2B)-adrenoceptors.