Back to Search
Start Over
New morpholine-containing pyrimidinones act on α-adrenoceptors.
- Source :
-
European journal of pharmacology [Eur J Pharmacol] 2024 Sep 05; Vol. 978, pp. 176788. Date of Electronic Publication: 2024 Jul 06. - Publication Year :
- 2024
-
Abstract
- Drugs that act on α-adrenoceptors may contain morpholine and pyrimidinone heterocycles. The aim of this study was to synthesize a series of pyrimidinones (S6a-e and S8) and characterize their α-adrenoceptor activity. Cytotoxicity assays (MTT and LDH) were performed in A7r5 and HUVECs. Concentration-effect curves to phenylephrine (Phe) were performed in rat aortic rings in the presence of compounds S6a-e and S8 or vehicle. Nitric oxide (NO) production and NO stable metabolic products, nitrite and nitrate, expressed as total nitrogen oxides (NOx) were assessed in HUVECs by confocal microscopy with the DAF-2DA probe and by the Griess reaction, respectively. Molecular docking simulations were performed using the 6a compound and α <subscript>2A</subscript> -adrenoceptor. In the evaluated conditions, the percentage of viable cells and the release of LDH were similar between control cells and cells exposed to the tested pyrimidinones. S6d, S6e, S8, and the positive control prazosin (but not S6a, S6b, and S6c) decreased Phe-induced contractions in endothelium-denuded aortic rings. S6a, S6b, and S6c decreased Phe-induced contractions in endothelium-intact aortic rings. The effect of S6a was abolished by L-NAME. NO production and NOx levels were inhibited in the presence of the α <subscript>2</subscript> receptor antagonist yohimbine and the NOS inhibitor L-NAME. The 6a docking simulation estimated that the mean binding free energy of the compound was lower than the estimated value for yohimbine. These data suggest that S6d, S6e, and S8 may be α <subscript>1</subscript> -adrenoceptor antagonists while S6a acts as an agonist of α <subscript>2</subscript> -adrenoceptors.<br />Competing Interests: Declaration of competing interest The authors of the manuscript entitled “New morpholine-containing pyrimidinones act on alpha-adrenergic receptors” declare that they have no conflict of interest.<br /> (Copyright © 2024 Elsevier B.V. All rights reserved.)
- Subjects :
- Animals
Humans
Rats
Nitric Oxide metabolism
Male
Receptors, Adrenergic, alpha-2 metabolism
Cell Line
Aorta drug effects
Aorta cytology
Aorta metabolism
Rats, Wistar
Molecular Docking Simulation
Human Umbilical Vein Endothelial Cells drug effects
Pyrimidinones pharmacology
Pyrimidinones chemistry
Morpholines pharmacology
Morpholines chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1879-0712
- Volume :
- 978
- Database :
- MEDLINE
- Journal :
- European journal of pharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 38977175
- Full Text :
- https://doi.org/10.1016/j.ejphar.2024.176788