The unusual binding properties of the endothelin receptor antagonist CGS 27830 distinguishes receptor/agonist interactions.

CGS 27830 [meso-1,4-dihydro-5-methoxycarbonyl-2,6-dimethyl-4-(3- nitrophenyl)-3-pyridine carboxylic acid anhydride] is a nonpeptidic, insurmountable, endothelin (ET) receptor antagonist with approximately 10- to 20-fold selectivity for ETA receptors. CGS 27830 exhibits unusual binding properties which depend on the receptor and ligand: standard saturation binding experiments (coincubation of membranes with ligand in the absence or presence of antagonist) suggest that CGS 27830 is a competitive inhibitor of [125I]IRL 1620 binding to ETB receptors in rat cerebellar membranes (i.e., there was a change of apparent Kd with no change of maximum binding), but a noncompetitive inhibitor of [125I]IRL 1620 binding to ETB receptors in rat lung membranes (i.e., significant loss of total binding was observed). Although the antagonist appears to be a noncompetitive inhibitor of [125I]IRL 1620 binding to ETB receptors in rat lung membranes, CGS 27830 appears to be a competitive inhibitor of [125I]ET-1 binding to the same receptors as well as to ETA receptors in A7r5 cell membranes. Thus, CGS 27830 can distinguish [125I]IRL 1620 binding to ETB receptors in rat cerebellar and lung membranes, but not ET-1 binding to ETB receptors in these tissues. These unusual binding properties demonstrate that rat lung and cerebellum ETB receptors interact differently with IRL 1620 or ET-1.