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) A R) by (-)-adrenaline in CHO-K1 cells transiently co-expressing a chimeric G (alpha qil) protein induced a rapid. transient Ca2+ response with a high-ma gnitude followed by a low-magnitude phase which continued throughout the re corded 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 Ca2+ response [E-max (%) versus 10 muM (-)-adrenaline]: UK 14304 (102+/-4)=talipexole (101 +/- 3)=(-)-adre naline(100)= d-medetomidine (98 +/- 1)> oxymetazoline (81 +/- 4) similar or equal to clonidine(75 +/- 5). 3 The methoxy- (RX 821002) and ethoxy-derivatives (RX 811059) of idazoxan a nd the dexefaroxan analogue atipamezole were fully effective as antagonists of both the high- and the low-magnitude Ca2+ response. However, though act ing as full antagonists of the high-magnitude response, the further putativ e 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 antagonis m of the low-magnitude Ca2+ response for structurally related alpha (2) AR ligands.