The new quinazoline derivative (N2-methyl-N4-[(thiophen-2-yl)methyl]quinazoline-2,4-diamine) vasodilates isolated mesenteric arteries through endothelium-independent mechanisms and has acute hypotensive effects in Wistar rats

Usana Chatturong; Krongkarn Chootip; Hélène Martin; Maude Tournier-Nappey; Kornkanok Ingkaninan; Prapapan Temkitthawon; Saharat Sermsenaphorn; Thanachon Somarin; Adchatawut Konsue; M Paul Gleeson; Perle Totoson; Céline Demougeot

doi:10.1016/j.ejphar.2023.175829

The new quinazoline derivative (N²-methyl-N⁴-[(thiophen-2-yl)methyl]quinazoline-2,4-diamine) vasodilates isolated mesenteric arteries through endothelium-independent mechanisms and has acute hypotensive effects in Wistar rats

Eur J Pharmacol. 2023 Aug 15:953:175829. doi: 10.1016/j.ejphar.2023.175829. Epub 2023 Jun 10.

Affiliations

¹ Department of Physiology, Faculty of Medical Science and Center of Excellence for Innovation in Chemistry, Naresuan University, Phitsanulok, 65000, Thailand; Université de Franche-Comté, PEPITE, Besançon, 25030, France.
² Department of Physiology, Faculty of Medical Science and Center of Excellence for Innovation in Chemistry, Naresuan University, Phitsanulok, 65000, Thailand. Electronic address: krongkarnc@nu.ac.th.
³ Université de Franche-Comté, PEPITE, Besançon, 25030, France.
⁴ Department of Pharmaceutical Chemistry and Pharmacognosy, Faculty of Pharmaceutical Sciences and Center of Excellence for Innovation in Chemistry, Naresuan University, Phitsanulok, 65000, Thailand.
⁵ Department of Biomedical Engineering, Faculty of Engineering, King Mongkut's Institute of Technology, Ladkrabang, Bangkok, 10520, Thailand.

PMID: 37307938
DOI: 10.1016/j.ejphar.2023.175829

Abstract

During the screening of new N²,N⁴-disubstituted quinazoline 2,4-diamines as phosphodiesterase-5 inhibitors and pulmonary artery vasodilators, one N²-methyl-N⁴-[(thiophen-2-yl)methyl]quinazoline-2,4-diamine (compound 8) presented a greater selectivity for systemic than pulmonary vasculature. The present study aimed to characterize its vasorelaxant and hypotensive effects in Wistar rats. Vasorelaxant effects of compound 8 and underlying mechanisms were evaluated on isolated mesenteric arteries. Acute hypotensive effect was evaluated in anesthetized rats. Additionally, cell viability and cytochrome P450 (CYP) activities were studied in rat isolated hepatocytes. Nifedipine was used as a comparator. Compound 8 induced a strong vasorelaxant effect, similar to nifedipine. This was unaffected by endothelium removal but was decreased by inhibitors of guanylate cyclase (ODQ) and K_Ca channel (iberiotoxin). Compound 8 enhanced sodium nitroprusside-induced relaxation, but inhibited vasoconstriction evoked by α₁-adrenergic receptor activation and extracellular Ca²⁺ influx via receptor-operated Ca²⁺ channels. Acute intravenous infusion of compound 8 (0.05 and 0.1 mg/kg) produced hypotension. It showed similar potency to nifedipine for lowering diastolic and mean arterial blood pressure, but less so for the effect on systolic blood pressure. Compound 8 had no effect on hepatocyte viability and CYP activities except at high concentration (10 μM) at which a weak inhibitory effect on CYP1A and 3A was observed. In conclusion, this study identified a N²-methyl-N⁴-[(thiophen-2-yl)methyl]quinazoline-2,4-diamine with a potent vasodilator effect on resistance vessels, leading to an acute hypotensive effect and a low risk of liver toxicity or drug-drug interactions. These vascular effects were mediated mainly through sGC/cGMP pathway, opening of K_Ca channels, and inhibition of calcium entry.

Keywords: CYP activities; Hypotensive effect; Mesenteric artery; Quinazoline derivatives; Vasorelaxation.

MeSH terms

Animals
Diamines / chemistry
Hypotension
Male
Mesenteric Arteries* / chemistry
Quinazolines / chemistry
Quinazolines / isolation & purification
Quinazolines / pharmacology
Rats
Rats, Wistar
Signal Transduction / drug effects
Vasodilator Agents / chemistry
Vasodilator Agents / isolation & purification
Vasodilator Agents / pharmacology

Substances

Vasodilator Agents
Quinazolines
Diamines