Next Article in Journal
Regioselective Fluorination of 7-Oxo-1,2,4-benzotriazines Using Selectfluor
Previous Article in Journal
Assessing Parameter Suitability for the Strength Evaluation of Intramolecular Resonance Assisted Hydrogen Bonding in o-Carbonyl Hydroquinones
Article Menu
Issue 2 (January-2) cover image

Export Article

Open AccessArticle
Molecules 2019, 24(2), 281; https://doi.org/10.3390/molecules24020281

Elucidation of Vasodilation Response and Structure Activity Relationships of N2,N4-Disubstituted Quinazoline 2,4-Diamines in a Rat Pulmonary Artery Model

1
Department of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Naresuan University, Phitsanulok 65000, Thailand
2
Department of Chemistry, Faculty of Science, Kasetsart University, Bangkok 10900, Thailand
3
Department of Biochemistry, Faculty of Science, Kasetsart University, Bangkok 10900, Thailand
4
Division of Pharmaceutical Sciences, School of Pharmaceutical Sciences, University of Phayao, Phayao 56000, Thailand
5
Department of Pharmaceutical Chemistry and Pharmacognosy, Faculty of Pharmaceutical Sciences and Center of Excellence for Innovation in Chemistry, Naresuan University, Phitsanulok 65000, Thailand
6
Department of Biomedical Engineering, Faculty of Engineering, King Mongkut’s Institute of Technology, Ladkrabang, Bangkok 10520, Thailand
7
Department of Physiology, Faculty of Medical Science, Naresuan University, Phitsanulok 65000, Thailand
*
Authors to whom correspondence should be addressed.
Received: 20 December 2018 / Revised: 10 January 2019 / Accepted: 10 January 2019 / Published: 14 January 2019
(This article belongs to the Section Medicinal Chemistry)
Full-Text   |   PDF [3405 KB, uploaded 14 January 2019]   |  

Abstract

Pulmonary arterial hypertension (PAH) is a rare and progressive disease arising from various etiologies and pathogenesis. PAH decreases life expectancy due to pulmonary vascular remodeling, elevation of mean pulmonary arterial pressure, and ultimately progresses to heart failure. While clinical treatments are available to reduce the associated symptoms, a complete cure has yet to be found. Phosphodiesterase-5 (PDE-5) inhibition has been identified as a possible intervention point in PAH treatment. The functional vasodilation response to N2,N4-diamino quinazoline analogues with differing PDE-5 inhibitory activities and varying physicochemical properties were assessed in both endothelium-intact and denuded rat pulmonary arteries to gain greater insight into their mode of action. All analogues produced vasorelaxant effects with EC50s ranging from 0.58 ± 0.22 µM to ˃30 µM. It was observed that vasodilation response in intact vessels was highly correlated with that of denuded vessels. The ~10% drop in activity is consistent with a loss of the nitric oxide mediated cyclic guanosine monophosphate (NO/cGMP) pathway in the latter case. A moderate correlation between the vasodilation response and PDE-5 inhibitory activity in the intact vessels was observed. Experimental protocol using the alpha-adrenergic (α1) receptor agonist, phenylephrine (PE), was undertaken to assess whether quinazoline derivatives showed competitive behavior similar to the α1 receptor blocker, prazosin, itself a quinazoline derivative, or to the PDE-5 inhibitor, sildenafil. Competitive experiments with the α1-adrenergic receptor agonist point to quinazoline derivatives under investigation here act via PDE-5 inhibition and not the former. The pre-incubation of pulmonary arterial rings with quinazoline test compounds (10 μM) reduced the contractile response to PE around 40–60%. The most promising compound (9) possessed ~32 folds higher selectivity in terms of vasodilation to its mammalian A549 cell cytotoxicity. This study provides experi0 0mental basis for PDE-5 inhibition as the mode of action for vasodilation by N2,N4-diamino quinazoline analogues along with their safety studies that may be beneficial in the treatment of various cardiovascular pathologies. View Full-Text
Keywords: vasodilation; rat pulmonary artery; PDE-5 inhibitor; N2,N4-diamino quinazoline; cheminformatics vasodilation; rat pulmonary artery; PDE-5 inhibitor; N2,N4-diamino quinazoline; cheminformatics
Figures

Graphical abstract

This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

Supplementary material

SciFeed

Share & Cite This Article

MDPI and ACS Style

Paracha, T.U.; Pobsuk, N.; Salaloy, N.; Suphakun, P.; Pekthong, D.; Hannongbua, S.; Choowongkomon, K.; Khorana, N.; Temkitthawon, P.; Ingkaninan, K.; Gleeson, M.P.; Chootip, K. Elucidation of Vasodilation Response and Structure Activity Relationships of N2,N4-Disubstituted Quinazoline 2,4-Diamines in a Rat Pulmonary Artery Model. Molecules 2019, 24, 281.

Show more citation formats Show less citations formats

Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Related Articles

Article Metrics

Article Access Statistics

1

Comments

[Return to top]
Molecules EISSN 1420-3049 Published by MDPI AG, Basel, Switzerland RSS E-Mail Table of Contents Alert
Back to Top