Exploring the antiplatelet activity of serotonin 5-HT2A receptor antagonists bearing 6-fluorobenzo[d]isoxazol-3-yl)propyl) motif– as potential therapeutic agents in the prevention of cardiovascular diseases

Marcinkowska, Monika; Kubacka, Monika; Zagórska, Agnieszka; Jaromin, Anna; Fajkis-Zajączkowska, Nikola; Kołaczkowski, Marcin

doi:10.1016/j.biopha.2021.112424

Cited by 7 publications

(11 citation statements)

References 34 publications

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“…We also examined the effect of the 5HT 2A RAb on collagen-induced aggregation. Our results show, as was previously documented with small molecule 5HT 2A R antagonists [ 32 , 33 , 34 , 35 ], that the 5HT 2A RAb did significantly inhibit collagen-induced aggregation ( Figure 2 D). As one would predict, 15 µM 5-HT-induced platelet shape change was inhibited by the 100 nM of 5HT 2A RAb ( Figure 2 A).…”

Section: Resultssupporting

confidence: 90%

“…The latter observation is contrary to clopidogrel (Plavix ® ), which is known to inhibit non-ADP pathways [ 55 , 56 ]. Of note however, the 5HT 2A RAb did impair collagen-dependent aggregation, which was also found to be the case with small molecule inhibitors of the 5HT 2A R [ 32 , 33 , 34 , 35 ]. This observation is consistent with the critical role serotonin plays in the collagen-dependent aggregation response [ 32 , 33 , 34 , 35 ].…”

Section: Discussionmentioning

confidence: 85%

“…Of note however, the 5HT 2A RAb did impair collagen-dependent aggregation, which was also found to be the case with small molecule inhibitors of the 5HT 2A R [ 32 , 33 , 34 , 35 ]. This observation is consistent with the critical role serotonin plays in the collagen-dependent aggregation response [ 32 , 33 , 34 , 35 ]. Moreover, the 5HT 2A RAb was also found to inhibit the ability of serotonin to enhance agonist-induced secretion, GPIIb/IIIa activation, and PS exposure.…”

Section: Discussionmentioning

confidence: 85%

“…Thus, it is possible that the 5HT 2A RAb would also have potential clinical use. Finally, efforts to developed anti-5HT 2A R small molecule inhibitors are continuing to date [ 35 ], thereby validating the 5HT 2A R as an attractive therapeutic target [ 22 , 61 ].…”

Section: Discussionmentioning

confidence: 99%

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A Novel Antibody Targeting the Second Extracellular Loop of the Serotonin 5-HT2A Receptor Inhibits Platelet Function

Ramirez

Alarabi

Khasawneh

et al. 2022

IJMS

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Serotonin (5-hydroxytriptamine or 5-HT) is known to be a weak platelet agonist, and is involved in thrombus formation. While 5-HT cannot induce platelet aggregation on its own, when secreted from the alpha granules, it binds to its G-protein Coupled Receptor (GPCR; i.e., 5HT2AR), thereby acting to amplify platelet functional responses (e.g., aggregation). Thus, 5HT2AR-mediated responses are more involved in the secondary amplification of platelet aggregation in the growing thrombus. Therefore, even though 5-HT can be seen as a weak inducer of platelet activation, it is an important amplifier of aggregation triggered by agonists such as ADP, collagen, and epinephrine, thereby enhancing thrombogenesis. The 5HT2AR/5HT2A signaling pathway is of clinical interest to the scientific and medical communities as it has been implicated in the genesis of several forms of cardiovascular disorders. However, efforts to develop antagonists for 5HT2AR as therapeutic agents in cardiovascular diseases have thus far failed due to these reagents having deleterious side-effects, and/or to lack of selectivity, amongst other reasons. In light of research efforts that identified that the 5HT2AR ligand binding domain resides in the second extracellular loop (EL2; amino acids P209-N233), we developed an antibody, i.e., referred to as 5HT2ARAb, against the EL2 region, and characterized its pharmacological activity in the context of platelets. Thus, we utilized platelets from healthy human donors, as well as C57BL/6J mice (10–12 weeks old) to analyze the inhibitory effects of the 5HT2ARAb on platelet activation in vitro, ex vivo, and on thrombogenesis in vivo as well as on 5HT2AR ligand binding. Our results indicate that the 5HT2ARAb inhibits 5-HT-enhanced platelet activation in vitro and ex vivo, but has no apparent effects on that which is agonist-induced. The 5HT2ARAb was also found to prolong the thrombus occlusion time, and it did so without modulating the tail bleeding time, in mice unlike the P2Y12 antagonist clopidogrel and the 5HT2AR antagonist ketanserin. Moreover, it was found that the 5HT2ARAb does so by directly antagonizing the platelet 5HT2AR. Our findings document that the custom-made 5HT2ARAb exhibits platelet function blocking activity and protects against thrombogenesis without impairing normal hemostasis.

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Section: Resultssupporting

confidence: 90%

Section: Discussionmentioning

confidence: 85%

Section: Discussionmentioning

confidence: 85%

Section: Discussionmentioning

confidence: 99%

See 2 more Smart Citations

A Novel Antibody Targeting the Second Extracellular Loop of the Serotonin 5-HT2A Receptor Inhibits Platelet Function

Ramirez

Alarabi

Khasawneh

et al. 2022

IJMS

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“…[ 91 ] CVD, particularly those involving narrow or blocked small diameter vessels (SDBVs), have the highest morbidity worldwide. [ 112 ] Expanded polytetrafluoroethylene (ePTFE) artificial vessels with a small diameter (<6 mm) are currently considered to be a potential candidate to treat the aforementioned SDBVs. Unfortunately, ePTFE artificial vessels without the cover of fully fused endodermis generally lead to treatment failure due to thrombosis and restenosis in vivo.…”

Section: No‐generating Ggnsmentioning

confidence: 99%

The Advancement of Gas‐Generating Nanoplatforms in Biomedical Fields: Current Frontiers and Future Perspectives

et al. 2022

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Diverse gases (NO, CO, H2S, H2, etc.) have been widely applied in the medical intervention of various diseases, including cancer, cardiovascular disease, ischemia‐reperfusion injury, bacterial infection, etc., attributing to their inherent biomedical activities. Although many gases have many biomedical activities, their clinical use is still limited due to the rapid and free diffusion behavior of these gases molecules, which may cause potential side effects and/or ineffective treatment. Gas‐generating nanoplatforms (GGNs) are effective strategies to address the aforementioned challenges of gas therapy by preventing gas production or release at nonspecific sites, enhancing GGNs accumulation at targeted sites, and controlling gas release in response to exogenous (UV, NIR, US, etc.) or endogenous (H2O2, GSH, pH, etc.) stimuli at the lesion site, further maintaining gas concentration within the effective range and achieving the purpose of disease treatment. This review comprehensively summarizes the advancements of “state‐of‐the‐art” GGNs in the recent three years, with emphasis on the composition, structure, preparation process, and gas release mechanism of the nanocarriers. Furthermore, the therapeutic effects and limitations of GGNs in preclinical studies using cell/animal models are discussed. Overall, this review enlightens the further development of this field and promotes the clinical transformation of gas therapy.

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N‐Chlorosuccinimide‐Promoted One‐Pot Synthesis of Substituted 4,5‐Dihydroisoxazole‐5‐methanols in Aqueous Medium

Jia

Ablajan

2023

Adv Synth Catal

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Herein, a catalyst‐free method for synthesizing 4,5‐dihydroisoxazole‐5‐methanols is proposed, whereby isoxazolines are constructed through the NCS‐mediated 1,3‐dipolar cycloaddition reaction of aldoximes and allyl alcohol in the presence of K2CO3 at room temperature via a one‐pot route. The reaction was achieved in water medium to introduce a low‐cost direct protocol for synthesizing isoxazolines. This method offers advantages including the use of an oxidant‐free and transition metal‐free approach, broad scope of allyl alcohol and aldoxime substrates, room‐temperature reaction, good to higher yields (42–92%), and involvement of a gram‐scale synthesis.

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Exploring the antiplatelet activity of serotonin 5-HT2A receptor antagonists bearing 6-fluorobenzo[d]isoxazol-3-yl)propyl) motif– as potential therapeutic agents in the prevention of cardiovascular diseases

Cited by 7 publications

References 34 publications

A Novel Antibody Targeting the Second Extracellular Loop of the Serotonin 5-HT2A Receptor Inhibits Platelet Function

A Novel Antibody Targeting the Second Extracellular Loop of the Serotonin 5-HT2A Receptor Inhibits Platelet Function

The Advancement of Gas‐Generating Nanoplatforms in Biomedical Fields: Current Frontiers and Future Perspectives

N‐Chlorosuccinimide‐Promoted One‐Pot Synthesis of Substituted 4,5‐Dihydroisoxazole‐5‐methanols in Aqueous Medium

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