Selectivity of the imidazoline α‐adrenoceptor agonists (oxymetazoline and cirazoline) for human cloned α 1 ‐adrenoceptor subtypes

1 To investigate the structure‐activity relationships of α‐adrenoceptor agonists for the α 1 ‐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 α 1 ‐adrenoceptor subtypes (α 1a ‐, α 1b ‐, and α 1d ‐subtypes) 2 Radioligand binding studies with [ 125 I]‐HEAT showed that cirazoline and oxymetazoline had higher affinities at α 1a ‐subtype than at α 1b ‐ and (α 1d ‐subtypes, while noradrenaline had higher affinity at the α 1d ‐subtype than at α 1a ‐ and α 1b ‐subtypes. 3 In functional studies, cirazoline caused transients of cytosolic Ca 2+ concentrations ([Ca 2+ ] response) in a concentration‐dependent manner and developed a maximal response similar to that to noradrenaline in CHO cells expressing the α 1a ‐subtype, while it acted as a partial agonist at α 1b ‐ and α 1d ‐adrenoceptors. Oxymetazoline, on the other hand, was a weak agonist at α 1a ‐adrenoceptors, and has no intrinsic activity at the other subtypes. 4 Using the phenoxybenzamine inactivation method, the relationships between receptor occupancy and noradrenaline‐induced [Ca 2+ ] i response for α 1a ‐ and α 1d ‐subtypes were found to be linear, whereas it was moderately hyperbolic for the α 1b ‐subtype, indicating the absence of receptor reserves in CHO cells expressing α 1a ‐ and α 1d ‐subtypes while there exists a small receptor reserve for CHO cells expressing the α 1b ‐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 α 1 ‐adrenoceptor.