Departamento de Farmacología, Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad Universitaria, Coyoacán 04510, CDMX, México.
Departamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de México, Ciudad Universitaria, Coyoacán 04510, CDMX, México | Departamento de Farmacología, Centro de Investigación y de Estudios Avanzados del Instituto Politecnico Nacional (CINVESTAV), CDMX, México.
Cardiovasc Hematol Agents Med Chem. 2022;20(1):43-51. doi: 10.2174/1871525719666210427132808.
The aim of this study was to evaluate the in vitro effect of coumarin and 15 monosubstituted derivatives on the inhibition of human platelet aggregation induced by various proaggregatory agonists, particularly by epinephrine.
The emergence of residual platelet reactivity during the use of conventional antiplatelet agents (acetylsalicylic acid and clopidogrel) is one of the main causes of double therapy´s therapeutic failure. Platelet adrenoceptors participate in residual platelet reactivity. Therefore, it is necessary to develop new antiplatelet agents that inhibit epinephrine-induced platelet aggregation as a new therapeutic strategy. Information on the antiplatelet activity of coumarins in inhibiting epinephrine-induced aggregation is limited.
The objective of this study was to establish the structure-activity relationship (SAR) of coumarin derivatives with hydroxy, methoxy, and acetoxy groups in different positions of the coumarin nucleus to identify the most active molecules. Moreover, this study aimed to use in silico studies to suggest potential drug targets to which the molecules bind to produce antiplatelet effects.
The platelet aggregation was performed using a Lumi-aggregometer; the inhibitory activity of 16 compounds were evaluated by inducing the aggregation of human platelets (250 × 103/μl) with epinephrine (10 μM), collagen (2 μg/ml) or ADP (10 μM). The aggregation of control platelets was considered 100% of the response for each pro-aggregatory agonist.
Eleven molecules inhibited epinephrine-induced aggregation, with 3-acetoxycoumarin and 7-methoxycoumarin being the most active. Only coumarin inhibited collagen-induced platelet aggregation, but no molecule showed activity when using ADP as an inducer.
In silico studies suggest that most active molecules might have antagonistic interactions in the α2 and β2 adrenoceptors. The antiplatelet actions of these coumarins have the potential to reduce residual platelet reactivity and thus contribute to the development of future treatments for patients who do not respond adequately to conventional agents.
本研究旨在评估香豆素及其 15 种单取代衍生物对各种促聚集激动剂（特别是肾上腺素）诱导的人血小板聚集的体外抑制作用。
在使用传统抗血小板药物（乙酰水杨酸和氯吡格雷）期间出现的残留血小板反应性是双重治疗治疗失败的主要原因之一。血小板肾上腺素受体参与残留血小板反应性。因此，有必要开发新的抗血小板药物，以抑制肾上腺素诱导的血小板聚集作为新的治疗策略。关于香豆素抑制肾上腺素诱导的聚集的抗血小板活性的信息有限。
本研究旨在确定香豆素核中不同位置带有羟基、甲氧基和乙酰氧基的香豆素衍生物的结构-活性关系（SAR），以确定最活跃的分子。此外，本研究旨在使用计算机模拟研究来提出分子结合产生抗血小板作用的潜在药物靶点。
使用 Lumi-aggregometer 进行血小板聚集实验；通过诱导人血小板（250×103/μl）与肾上腺素（10 μM）、胶原（2 μg/ml）或 ADP（10 μM）聚集来评估 16 种化合物的抑制活性。每种促聚集激动剂诱导的对照血小板聚集被认为是 100%的反应。
有 11 种分子抑制了肾上腺素诱导的聚集，其中 3-乙酰氧基香豆素和 7-甲氧基香豆素最为活跃。只有香豆素抑制了胶原诱导的血小板聚集，但没有分子在使用 ADP 作为诱导剂时显示活性。
计算机模拟研究表明，大多数活性分子可能在α2 和β2 肾上腺素受体上具有拮抗相互作用。这些香豆素的抗血小板作用有可能降低残留血小板反应性，从而为开发未来对传统药物反应不足的患者的治疗方法做出贡献。
