s-9871 and dexefaroxan

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 alpha 2A-adrenoceptor (alpha 2A AR): 1) pertussis toxin-resistant guanosine 5'-O-(3-[35S]thio)triphosphate ([35S]GTP gamma S) binding responses mediated by either a recombinant G alpha oCys351Ile or G alpha 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 alpha 2A AR state in the copresence of a G alpha oCys351Ile protein but not G alpha i2Cys352Ile protein by monitoring [35S]GTP gamma S binding responses. Neither positive nor negative efficacy was observed for these compounds by monitoring the adenylate cyclase pathway at a presumably low-affinity alpha 2A AR state. The capacity of the dexefaroxan analogs to antagonize the (-)-epinephrine-mediated [35S]GTP gamma S binding response at a G alpha oCys351Ile protein was inversely correlated with their magnitude of intrinsic activity and unrelated to their ligand binding affinity for the alpha 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]GTP gamma S binding response. In conclusion, these data demonstrate that certain alpha2 AR ligands that are assumed to be antagonists, may yield dissimilar pharmacological responses, dependent on the investigated agonist-stimulated effector pathway.

Topics: Adrenergic alpha-Agonists; Adrenergic alpha-Antagonists; Animals; Benzofurans; Benzopyrans; Binding Sites; Brimonidine Tartrate; CHO Cells; Cricetinae; Cyclic AMP; Epinephrine; Guanosine 5'-O-(3-Thiotriphosphate); Humans; Idazoxan; Imidazoles; Pertussis Toxin; Quinoxalines; Rats; Receptors, Adrenergic, alpha-2; Sulfur Radioisotopes; Tumor Cells, Cultured