Novel serotonin 5-HT2A receptor antagonists derived from 4-phenylcyclohexane-5-spiro-and 5-methyl-5-phenyl-hydantoin, for use as potential antiplatelet agents

Article abstract of DOI:10.1007/s43440-021-00284-6

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 (IC₅₀ = 27.3?μM) being more active than sarpogrelate (IC₅₀ = 66.8?μM) and comparable with ketanserin (IC₅₀ = 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.