Monosubstituted Coumarins Inhibit Epinephrine-induced Platelet Aggregation
Por:
Jiménez-Orozco F.A., Galicia-Zapatero S., López-López E., Medina-Franco J.L., Cedeño F.L., Flores-García M., Mejia-Domínguez A.M., de la Peña-Díaz A.
Publicada:
1 ene 2022
Resumen:
Aim: 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. Background: 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. Objective: 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. Methods: 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. Results: 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. Conclusions: In silico studies suggest that most active molecules might have antagonistic interactions in the a2 and ß2 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. © 2022 Bentham Science Publishers.
Filiaciones:
Jiménez-Orozco F.A.:
Departamento de Farmacología, Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad Universitaria, Coyoacán, CDMX, 04510, Mexico
Galicia-Zapatero S.:
Departamento de Farmacología, Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad Universitaria, Coyoacán, CDMX, 04510, Mexico
López-López E.:
Departamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de México, Ciudad Universitaria, Coyoacán, CDMX, 04510, Mexico
Departamento de Farmacología, Centro de Investigación y de Estudios Avanzados del Instituto Politecnico Nacional (CINVESTAV), CDMX, Mexico
Medina-Franco J.L.:
Departamento de Farmacia, Facultad de Química, Universidad Nacional Autónoma de México, Ciudad Universitaria, Coyoacán, CDMX, 04510, Mexico
Cedeño F.L.:
Departamento de Química Orgánica, Facultad de Química, Universidad Nacional Autónoma de México, Ciudad Universitaria, Coyoacán, CDMX, 04510, Mexico
Flores-García M.:
Departamento de Biología Molecular, Instituto Nacional de Cardiología Ignacio Chávez, Tlalpan, CDMX, 14080, Mexico
Mejia-Domínguez A.M.:
Banco de Sangre, Instituto Nacional de Cardiología Ignacio Chávez, Tlalpan, CDMX, 14080, Mexico
de la Peña-Díaz A.:
Departamento de Farmacología, Facultad de Medicina, Universidad Nacional Autónoma de México, Ciudad Universitaria, Coyoacán, CDMX, 04510, Mexico
Departamento de Biología Molecular, Instituto Nacional de Cardiología Ignacio Chávez, Tlalpan, CDMX, 14080, Mexico
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