Novel serotonin 5-HT(2A) receptor antagonists derived from 4-phenylcyclohexane-5-spiro-and 5-methyl-5-phenyl-hydantoin, for use as potential antiplatelet agents

BACKGROUND: Antiplatelet drugs have been used in the treatment of acute coronary syndromes and for the prevention of recurrent events. Unfortunately, many patients remain resistant to the available antiplatelet treatment. Therefore, there is a clinical need to synthesize novel antiplatelet agents, which would be associated with different pathways of platelet aggregation, to develop an alternative or additional treatment for resistant patients. Recent studies have revealed that 5-HT(2A) receptor antagonists could constitute alternative antiplatelet therapy. METHODS: Based on the structures of the conventional 5-HT(2A) receptor ligands, two series of compounds with 4-phenylcyclohexane-5-spiro- or 5-methyl-5-phenyl-hydantoin core linked to various arylpiperazine moieties were synthesized and their affinity for 5-HT(2A) receptor was assessed. Further, we evaluated their antagonistic potency at 5-HT(2A) receptors using isolated rat aorta and cells expressing human 5-HT(2A) receptors. Finally, we studied their anti-aggregation effect and compared it with ketanserin and sarpogrelate, the reference 5-HT(2A) receptor antagonists. Moreover, the structure–activity relationships were studied following molecular docking to the 5-HT(2A) receptor model. RESULTS: Functional bioassays revealed some of the synthesized compounds to be moderate antagonists of 5-HT(2A) receptors. Among them, 13, 8-phenyl-3-(3-(4-phenylpiperazin-1-yl)propyl)-1,3-diazaspiro[4.5]decane-2,4-dione, inhibited collagen stimulated aggregation (IC(50) = 27.3 μM) being more active than sarpogrelate (IC(50) = 66.8 μM) and comparable with ketanserin (IC(50) = 32.1 μM). Moreover, compounds 2–5, 9–11, 13, 14 inhibited 5-HT amplified, ADP- or collagen-induced aggregation. CONCLUSIONS: Our study confirmed that the 5-HT(2A) antagonists effectively suppress platelet aggregation and remain an interesting option for the development of novel antiplatelet agents with an alternative mechanism of action. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s43440-021-00284-6.