b-Adrenergic receptors (b-ARs) are G protein-coupled receptors involved in important physiological and pathological processes related to blood pressure and cardiac activity. The inhibition of cardiac b1-ARs could be beneficial in myocardial hypertrophy, ischemia and failure. Several carbazole-based compounds have been described as promising b-blockers. Herein, we investigate the capability of a carbazole derivative and three simplified indole analogs to interact with the active binding site of b1-AR by molecular docking studies. In the light of the obtained results, our compounds were tested by biological assays in H9c2 cardiomyocytes exposed to isoproterenol (ISO) to confirm their potential as b1-blockers agents, and two of them (8 and 10) showed interesting and promising properties. In particular, these compounds were effective against ISO-dependent in vitro cardiac hypertrophy, even at concentrations lower than the known b-AR antagonist propranolol. Overall, the data suggest that the indole derivatives 8 and 10 could act as potent b1-blockers and, active at low doses, could elicit limited side effects

Carbazole and simplified derivatives: Novel tools toward β-adrenergic receptors targeting

Grande F.;De Bartolo A.;Occhiuzzi M. A.;Rocca C.;Rago V.;Angelone T.;Sinicropi M. S.
2021-01-01

Abstract

b-Adrenergic receptors (b-ARs) are G protein-coupled receptors involved in important physiological and pathological processes related to blood pressure and cardiac activity. The inhibition of cardiac b1-ARs could be beneficial in myocardial hypertrophy, ischemia and failure. Several carbazole-based compounds have been described as promising b-blockers. Herein, we investigate the capability of a carbazole derivative and three simplified indole analogs to interact with the active binding site of b1-AR by molecular docking studies. In the light of the obtained results, our compounds were tested by biological assays in H9c2 cardiomyocytes exposed to isoproterenol (ISO) to confirm their potential as b1-blockers agents, and two of them (8 and 10) showed interesting and promising properties. In particular, these compounds were effective against ISO-dependent in vitro cardiac hypertrophy, even at concentrations lower than the known b-AR antagonist propranolol. Overall, the data suggest that the indole derivatives 8 and 10 could act as potent b1-blockers and, active at low doses, could elicit limited side effects
2021
b-blockers; carbazole; indole; molecular docking; H9c2 cells; cardiac hypertrophy
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/20.500.11770/323103
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