Evaluation of pharmacokinetics, pharmacodynamics, and toxicity of potential quinazoline bronchodilators derived from vasicinone.

Abstract

Various synthetic modifications of the alkaloid (-)-vasicinone are known to exhibit a remarkable bronchodilatory effect. This study aimed to examine selected pharmacological and toxicological properties of 2 quinazolines derived from vasicinone with previously proven bronchodilatory action to consider their potential applicability for further preclinical development. Both compounds were found to have relatively low in vitro toxicity in a standard hepatic cell model. Pharmacokinetic studies in rats using oral and intravenous administration showed significant differences in oral availability (0.66 ± 0.11% vs 0.36 ± 0.18%), distribution volume, and elimination parameters of the 2 tested agents (for all parameters, P < .05). The different pharmacokinetic properties offer the possibility to select more convenient compounds for inhalation or systemic administration in further stages of development. The performed pharmacodynamic studies using an in vitro model showed that the tested quinazolines bind to the allosteric site on muscarinic acetylcholine receptors with micromolar affinity (pK_B higher than pK_I for M₁ and M₃ receptors, P < .05) and exert functional antagonism of carbachol-induced response. The main effect is not accompanied by a concomitant antibiotic effect. The proven inhibition of muscarinic receptors including the M₃ subtype is analogous to the effects of clinically used anticholinergic bronchodilators. Therefore, the findings suggest that the bronchodilating effect of the tested compounds is likely mediated by a similar mechanism. The muscarinic receptor blocking effect based on allosteric binding to the receptors may potentially allow the development of a new group of highly selective M₃ antagonists. SIGNIFICANCE STATEMENT: Two tested synthetic quinazoline derivatives with proven bronchodilator action exhibit allosteric binding to muscarinic receptors. Since the extracellular domain at which allosteric modulators commonly bind varies among subtypes of muscarinic receptors, this characteristic may allow further development of highly selective M₃ antagonists. The examined compounds exhibit low toxicity as well as no concomitant antimicrobial effect that would potentially affect the bronchial microbiome.