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.
Pauwels
P J
PJ
Department of Cellular and Molecular Biology, Centre de Recherche Pierre Fabre, 17, avenue Jean Moulin, 81106 Castres Cédex - France. peter.pauwels@pierre-fabre.com
Colpaert
F C
FC
D000322:Adrenergic Agonists / Q000494:pharmacology*; D018674:Adrenergic Antagonists / Q000494:pharmacology*; D000818:Animals; D001381:Azepines / Q000494:pharmacology; D000068438:Brimonidine Tartrate; D016466:CHO Cells; D002118:Calcium / Q000378:metabolism; D003000:Clonidine / Q000494:pharmacology; D006224:Cricetinae; D004274:DNA, Recombinant / Q000235:genetics; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D004837:Epinephrine / Q000494:pharmacology; D019206:GTP-Binding Protein alpha Subunits, Gi-Go / Q000235:genetics; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D020962:Heterotrimeric GTP-Binding Proteins / Q000235:genetics; D019329:Idazoxan / Q000031:analogs & derivatives* / Q000494:pharmacology; D007700:Kinetics; D020926:Medetomidine / Q000494:pharmacology; D051379:Mice; D010109:Oxymetazoline / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology; D051381:Rats; D018341:Receptors, Adrenergic, alpha-2 / Q000187:drug effects* / Q000235:genetics; D011993:Recombinant Fusion Proteins / Q000235:genetics; D014162:Transfection
C547774:ADRA2C protein, human; C547775:Adra2c protein, mouse; D000322:Adrenergic Agonists; D018674:Adrenergic Antagonists; D001381:Azepines; D004274:DNA, Recombinant; D011810:Quinoxalines; D018341:Receptors, Adrenergic, alpha-2; D011993:Recombinant Fusion Proteins; D000068438:Brimonidine Tartrate; C024763:talipexole; D010109:Oxymetazoline; C065483:ethoxyidazoxan; D019206:GTP-Binding Protein alpha Subunits, Gi-Go; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D020962:Heterotrimeric GTP-Binding Proteins; D003000:Clonidine; D020926:Medetomidine; D002118:Calcium; D019329:Idazoxan; D004837:Epinephrine