Pharmacological Evaluation of Selectiveα2c-Adrenergic Agonists in Experimental Animal Models of Nasal Congestion

Abstract

Nasal congestion is one of the most troublesome symptoms of many upper airways diseases. We characterized the effect of selective a2c-adrenergic agonists in animal models of nasal congestion. In porcine mucosa tissue, compound A and compound B contracted nasal veins with only modest effects on arteries. In in vivo experiments, we examined the nasal decongestant dose-response characteristics, pharmacokinetic/ pharmacodynamic relationship, duration of action, potential development of tolerance, and topical efficacy of a2c-adrenergic agonists. Acoustic rhinometry was used to determine nasal cavity dimensions following intranasal compound 48/80 (1%, 75 ml). In feline experiments, compound 48/80 decreased nasal cavity volume and minimum cross-sectional areas by 77% and 40%, respectively. Oral administration of compound A (0.1-3.0 mg/kg), compound B (0.3-5.0 mg/kg), and d-pseudoephedrine (0.3 and 1.0 mg/kg) produced dose-dependent decongestion. Unlike dpseudoephedrine, compounds A and B did not alter systolic blood pressure. The plasma exposure of compound A to produce a robust decongestion (EC 80 ) was 500 nM, which related well to the duration of action of approximately 4.0 hours. No tolerance to the decongestant effect of compound A (1.0 mg/kg p.o.) was observed. To study the topical efficacies of compounds A and B, the drugs were given topically 30 minutes after compound 48/80 (a therapeutic paradigm) where both agents reversed nasal congestion. Finally, nasal-decongestive activity was confirmed in the dog. We demonstrate that a2c-adrenergic agonists behave as nasal decongestants without cardiovascular actions in animal models of upper airway congestion.

The C-terminal half of the α2C-adrenoceptor determines the receptor's membrane expression level and drug selectivity

“…Recently, an 2C -agonist has been investigated as nasal decongestant in animal models with the aim of developing a decongestant without cardiovascular actions [48].…”