Design,synthesis and pharmacological evaluation of 6-hydroxy-4-methylquinolin-2(1H)-one derivatives as inotropic agents |
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Authors: | Hamid Sadeghian Mohammad Reza Saberi Reza Shafiee Nick Azar Hosseini Mehdi Bakavoli |
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Affiliation: | 1. Department of Chemistry, Faculty of Sciences, Ferdowsi University of Mashhad, Mashhad, I. R. Iran;2. School of Pharmacy, Pharmaceutical Research Center, Mashhad University of Medical Sciences, BuAli Square, Mashhad, I. R. Iran;3. Deptartment of Pharmacology, School of Medicine, Pharmacological Research Center of Medicinal Plants, Mashhad University of Medical Sciences, Mashhad, I. R. Iran |
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Abstract: | Selective PDE3 inhibitors improve cardiac contractility and may be used in congestive heart failure. However, their proarrhythmic potential is the most important side effect. In this research we designed, synthesized and evaluated the potential cardiotonic activity of thirteen PDE3 inhibitors (4-[(4-methyl-2-oxo-1,2-dihydro-6-quinolinyl)oxy]butanamide analogs) using the spontaneously beating atria model. The design strategy was based on the structure of cilostamide, a selective PDE3 inhibitor. In each experiment, atrium of reserpine-treated rat was isolated and the contractile and chronotropic effects of a synthetic compounds were assessed. All experiments were carried out in comparison with IBMX, amrinone and cilostamide as standard compounds. The results showed that, among the new compounds, the best pharmacological profile was obtained with the compound 6-[4-(4-methylpiperazine-1-yl)-4-oxobutoxy]-4-methylquinolin-2(1H)-one, 4j, which displayed selectivity for increasing the force of contraction (165 ± 4% change over the control) rather than the frequency rate (115 ± 7% change over the control) at 100 μM and potent inhibitory activity of PDE3 with IC50 = 0.20 μM. |
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Keywords: | PDE3 inhibitor cilostamide inotropic activity Rat atria Isoprenaline Docking SAR |
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