PT - JOURNAL ARTICLE AU - Petrus J. Pauwels AU - Isabelle Rauly AU - Thierry Wurch TI - Dissimilar Pharmacological Responses by a New Series of Imidazoline Derivatives at Precoupled and Ligand-Activated α<sub>2A</sub>-Adrenoceptor States: Evidence for Effector Pathway-Dependent Differential Antagonism AID - 10.1124/jpet.102.048215 DP - 2003 Jun 01 TA - Journal of Pharmacology and Experimental Therapeutics PG - 1015--1023 VI - 305 IP - 3 4099 - http://jpet.aspetjournals.org/content/305/3/1015.short 4100 - http://jpet.aspetjournals.org/content/305/3/1015.full SO - J Pharmacol Exp Ther2003 Jun 01; 305 AB - Whereas agonist-directed differential signaling at a single receptor subtype has become an accepted pharmacological concept, distinct behaviors by ligands that are assumed to be antagonists is less documented. The intrinsic activity and capacity of antagonism for a new series of imidazoline-derived adrenergic ligands analogous to dexefaroxan were investigated by measuring two distinct signaling pathways at the recombinant human α2A-adrenoceptor (α2A AR): 1) pertussis toxin-resistant guanosine 5′-O-(3-[35S]thio)triphosphate ([35S]GTPγS) binding responses mediated by either a recombinant GαoCys351Ile or Gαi2Cys352Ile protein in CHO-K1 cells, and 2) inhibition of cAMP formation in a stably transfected C6-glial cell line. Ligands could be differentiated as inverse agonists [i.e., 2-(4-methoxy-2-ethyl-2,3-dihydrobenzofuran-2-yl)-4,5-dihydro-1H-imidazole; RX 851062], neutral antagonists [i.e., 2-(4-hydroxy-2-ethyl-2,3-dihydrobenzofuran-2-yl)-4,5-dihydro-1H-imidazole; RX 851057], partial [i.e., 2-(4-chloro-2,3-dihydrobenzofuran-2-yl)-4,5-dihydro-1H-imidazole; RX 821008], and high-efficacy [i.e., 2-(6,7-dichloro-2,3-dihydrobenzofuran-2-yl)-4,5-dihydro-1H-imidazole; RX 821010] agonists at a precoupled α2A AR state in the copresence of a GαoCys351Ile protein but not Gαi2Cys352Ile protein by monitoring [35S]GTPγS binding responses. Neither positive nor negative efficacy was observed for these compounds by monitoring the adenylate cyclase pathway at a presumably low-affinity α2A AR state. The capacity of the dexefaroxan analogs to antagonize the (-)-epinephrine-mediated [35S]GTPγS binding response at a GαoCys351Ile protein was inversely correlated with their magnitude of intrinsic activity and unrelated to their ligand binding affinity for the α2A AR. On the other hand, their capacity to antagonize either (-)-epinephrine or 5-bromo-6-(2-imidazolin-2-ylamino)quinoxaline tartrate (UK 14304)-mediated inhibition of forskolin-stimulated cAMP formation was not related with the rank order of antagonist capacity for the (-)-epinephrine-mediated [35S]GTPγS binding response. In conclusion, these data demonstrate that certain α2 AR ligands that are assumed to be antagonists, may yield dissimilar pharmacological responses, dependent on the investigated agonist-stimulated effector pathway. The American Society for Pharmacology and Experimental Therapeutics