Key result
Novel 5-HT2A antagonist Compound 13 inhibits collagen-stimulated platelet aggregation better than sarpogrelate, matching ketanserin.
Why the study?
Many patients remain resistant to available antiplatelet treatments, creating a need for novel agents targeting different platelet aggregation pathways.
Novel synthesized 5-HT2A receptor antagonists demonstrated effective suppression of platelet aggregation in vitro, highlighting their potential as alternative antiplatelet agents.
May support 5-HT2A antagonists in resistant ACS; hypothesis-generating pending larger trials.
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-HT2A receptor antagonists could constitute alternative antiplatelet therapy. Methods Based on the structures of the conventional 5-HT2A 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-HT2A receptor was assessed. Further, we evaluated their antagonistic potency at 5-HT2A receptors using isolated rat aorta and cells expressing human 5-HT2A receptors. Finally, we studied their anti-aggregation effect and compared it with ketanserin and sarpogrelate, the reference 5-HT2A receptor antagonists. Moreover, the structure–activity relationships were studied following molecular docking to the 5-HT2A receptor model. Results Functional bioassays revealed some of the synthesized compounds to be moderate antagonists of 5-HT2A 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-HT2A antagonists effectively suppress platelet aggregation and remain an interesting option for the development of novel antiplatelet agents with an alternative mechanism of action.
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Czopek et al. (2021) studied this question. Novel serotonin 5-HT2A receptor antagonists (e.g., compound 13) vs. ketanserin and sarpogrelate was evaluated on collagen stimulated aggregation. Compound 13, a novel 5-HT2A receptor antagonist, inhibited collagen-stimulated platelet aggregation (IC50 = 27.3 μM) more effectively than sarpogrelate and comparably to ketanserin.
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