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.
Chin
M H
MH
Ciba-Geigy Corporation, Research Department, Summit, New Jersey, USA.
Cioffi
C L
CL
Garay
M
M
Neale
R F
RF
Shetty
S S
SS
DelGrande
D
D
Mugrage
B
B
Sills
M A
MA
Lipson
K E
KE
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology; D002462:Cell Membrane / Q000187:drug effects / Q000648:ultrastructure; D002478:Cells, Cultured; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D004095:Dihydropyridines / Q000494:pharmacology*; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000378:metabolism; D066298:In Vitro Techniques; D007457:Iodine Radioisotopes; D007700:Kinetics; D008024:Ligands; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000648:ultrastructure; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D010446:Peptide Fragments / Q000378:metabolism; D011485:Protein Binding / Q000187:drug effects; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D017466:Receptors, Endothelin / Q000819:agonists* / Q000378:metabolism
D004095:Dihydropyridines; D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D007457:Iodine Radioisotopes; D008024:Ligands; D010446:Peptide Fragments; D017466:Receptors, Endothelin; C074308:sovateltide; C097746:CGS 27830