Characterization of some carbostyril congeners having novel beta-adrenoreceptor agonist properties

The interaction of two new derivatives of 8-hydroxy-carbostyril with the beta-adrenoreceptor system was partially characterized using isolated membranes, cultured cells, and animals. These carbostyril congeners contained an amino (Carbo-Am) or bromoacetamido (Carbo-Br) moiety in the para position of the phenyl ring. In rat reticulocyte membranes, binding studies under different conditions with [125I]iodocyanopindolol revealed that Carbo-Br and Carbo-Am were 17 to 107-fold more potent that (-)isoproterenol Carbo-Am and Carbo-Br were 13.5 and 30-fold, respectively, more potent than (-)isoproterenol at stimulating adenylate cyclase activity, but exhibited the same intrinsic activity. Adenylate cyclase activation by Carbo-Br, Carbo-Am or (-)isoproterenol was blocked with concurrent addition of propranolol. If, however, propranolol was added 7 min into the assay, further cAMP production by Carbo-Br and Carbo-Am was unaffected while further cAMP production by (-)isoproterenol was immediately blocked. Both Carbo-Br and Carbo-Am induced a receptor loss that was blocked by nadolol. The tightly bound Carbo-Am could be partially dissociated by heat treatment whereas Carbo-Br could not