Selectivity of the imidazoline alpha -adrenoceptor agonists (oxymetazoline and cirazoline) for human cloned alpha sub(1)-adrenoceptor subtypes

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