Selectivity of the imidazoline α‐adrenoceptor agonists (oxymetazoline and cirazoline) for human cloned α1‐adrenoceptor subtypes

1 To investigate the structure‐activity relationships of α‐adrenoceptor agonists for the α1‐adrenoceptor subtypes*, we have compared the imidazoline class of compounds, oxymetazoline and cirazoline, with the phenethylamine, noradrenaline, in their affinities and also in their intrinsic activities in Chinese hamster ovary (CHO) cells stably expressing the cloned human α1‐adrenoceptor subtypes (α1a‐, α1b‐, and α1d‐subtypes) 2 Radioligand binding studies with [125I]‐HEAT showed that cirazoline and oxymetazoline had higher affinities at α1a‐subtype than at α1b‐ and (α1d‐subtypes, while noradrenaline had higher affinity at the α1d‐subtype than at α1a‐ and α1b‐subtypes. 3 In functional studies, cirazoline caused transients of cytosolic Ca2+ concentrations ([Ca2+] response) in a concentration‐dependent manner and developed a maximal response similar to that to noradrenaline in CHO cells expressing the α1a‐subtype, while it acted as a partial agonist at α1b‐ and α1d‐adrenoceptors. Oxymetazoline, on the other hand, was a weak agonist at α1a‐adrenoceptors, and has no intrinsic activity at the other subtypes. 4 Using the phenoxybenzamine inactivation method, the relationships between receptor occupancy and noradrenaline‐induced [Ca2+]i response for α1a‐ and α1d‐subtypes were found to be linear, whereas it was moderately hyperbolic for the α1b‐subtype, indicating the absence of receptor reserves in CHO cells expressing α1a‐ and α1d‐subtypes while there exists a small receptor reserve for CHO cells expressing the α1b‐subtype. 5 In summary, our data obtained in cells exclusively expressing a single receptor subtype support the idea that the relative role of agonist affinity and intrinsic activity may vary depending on the subtype of α1‐adrenoceptor.