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CELLULAR AND MOLECULAR

Dissimilar Pharmacological Responses by a New Series of Imidazoline Derivatives at Precoupled and Ligand-Activated _2A-Adrenoceptor States: Evidence for Effector Pathway-Dependent Differential Antagonism

Department of Cellular and Molecular Biology, Centre de Recherche Pierre Fabre, Castres, France

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 _2A-adrenoceptor (_2A AR): 1) pertussis toxin-resistant guanosine 5'-O-(3-[³⁵S]thio)triphosphate ([³⁵S]GTPS) binding responses mediated by either a recombinant G_oCys³⁵¹Ile or G_i2Cys³⁵²Ile 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 _2A AR state in the copresence of a G_oCys³⁵¹Ile protein but not G_i2Cys³⁵²Ile protein by monitoring [³⁵S]GTPS binding responses. Neither positive nor negative efficacy was observed for these compounds by monitoring the adenylate cyclase pathway at a presumably low-affinity _2A AR state. The capacity of the dexefaroxan analogs to antagonize the (-)-epinephrine-mediated [³⁵S]GTPS binding response at a G_oCys³⁵¹Ile protein was inversely correlated with their magnitude of intrinsic activity and unrelated to their ligand binding affinity for the _2A 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]GTPS binding response. In conclusion, these data demonstrate that certain ₂ AR ligands that are assumed to be antagonists, may yield dissimilar pharmacological responses, dependent on the investigated agonist-stimulated effector pathway.

Address correspondence to: Dr. Peter Pauwels, Department of Cellular and Molecular Biology, Centre de Recherche Pierre Fabre, 17, avenue Jean Moulin, 81106 Castres Cédex, France. E-mail. peter.pauwels{at}pierre-fabre.com