THE UNUSUAL BINDING-PROPERTIES OF THE ENDOTHELIN RECEPTOR ANTAGONIST CGS-27830 DISTINGUISHES RECEPTOR AGONIST INTERACTIONS/

CGS 27830 ycarbonyl-2,6-dimethyl-4-(3-nitrophenyl)3-pyridine carboxyli c acid anhydride] is a nonpeptidic, insurmountable, endothelin (ET) re ceptor antagonist with approximately 10- to 20-fold selectivity for ET (A) receptors. CGS 27830 exhibits unusual binding properties which dep end on the receptor and ligand: standard saturation binding experiment s (coincubation of membranes with ligand in the absence or presence of antagonist) suggest that CGS 27830 is a competitive inhibitor of [I-1 25]IRL 1620 binding to ET(B) receptors in rat cerebellar membranes (i. e., there was a change of apparent K-d with no change of maximum bindi ng), but a noncompetitive inhibitor of [I-125]IRL 1620 binding to ET(B ) receptors in rat lung membranes (i.e., significant loss of total bin ding was observed). Although the antagonist appears to be a noncompeti tive inhibitor of [I-125]IRL 1620 binding to ET(B) receptors in rat lu ng membranes, CGS 27830 appears to be a competitive inhibitor of [I-12 5]ET-1 binding to the same receptors as well as to ET(A) receptors in A7r5 cell membranes. Thus, CGS 27830 can distinguish [I-125]IRL 1620 b inding to ET(B) receptors in rat cerebellar and lung membranes, but no t ET-1 binding to ET(B) receptors in these tissues. These unusual bind ing properties demonstrate that rat lung and cerebellum ET(B) receptor s interact differently with IRL 1620 or ET-1.