Partial to complete antagonism by putative antagonists at the wild-type alpha(2C)-adrenoceptor based on kinetic analyses of agonist:antagonist interactions.

1. Activation of the recombinant human alpha(2C)-adrenoceptor (alpha(2C) AR) by (-)-adrenaline in CHO-K1 cells transiently co-expressing a chimeric G(alpha q/i1) protein induced a rapid, transient Ca(2+) response with a high-magnitude followed by a low-magnitude phase which continued throughout the recorded time period (15 min). 2. Activation of the alpha(2C) AR by various alpha(2) AR agonists revealed the following rank order of high-magnitude Ca(2+) response [E(max) (%) versus 10 microM (-)-adrenaline]: UK 14304 (102+/-4)=talipexole (101+/-3)=(-)-adrenaline (100)=d-medetomidine (98+/-1)>oxymetazoline (81+/-4) reverse similarclonidine (75+/-5). 3. The methoxy- (RX 821002) and ethoxy-derivatives (RX 811059) of idazoxan and the dexefaroxan analogue atipamezole were fully effective as antagonists of both the high- and the low-magnitude Ca(2+) response. However, though acting as full antagonists of the high-magnitude response, the further putative alpha(2) AR antagonists idazoxan (27%), SKF 86466 (29%) and dexefaroxan (59%) reversed the low-magnitude response only partially. 4. In conclusion, kinetic analyses of agonist : antagonist interactions at the alpha(2C) AR demonstrate a wide spectrum of partial to complete antagonism of the low-magnitude Ca(2+) response for structurally related alpha(2) AR ligands.