Characterization of a potent and selective endothelin-B receptor antagonist, IRL 2500.
IRL 2500 [N-(3,5-dimethylbenzoyl)-N-methyl-(D)-(4-phenylphenyl)-alany l-L- tryptophan] inhibited the binding of [125I]-endothelin-1 (ET-1) to human ETB (IC50 1.3 +/- 0.2 nM) and ETA (IC50 94 +/- 3 nM) receptors expressed in transfected Chinese hamster ovary (CHO) cells. In in vitro studies, IRL 2500 inhibited the sarafotoxin S6c (STX6c)-mediated contraction of the dog saphenous vein (pKb 7.77) and the STX6c-induced relaxation of the preconstricted rabbit mesenteric artery (pKb 6.92). In the anesthetized rat, IRL 2500 (10 mg/kg, i.v.) inhibited the initial transient decrease in mean arterial pressure (MAP) induced by the ETB-selective agonist IRL 1620 (0.5 nmol/kg, i.v.). IRL 2500 also attenuated the IRL 1620-mediated increase in renal vascular resistance (RVR) in the anesthetized rat. Therefore, IRL 2500 is a potent and selective ETB receptor antagonist that can be used to delineate ET responses mediated by the ETB receptor.
Balwierczak
J L
JL
Research Department, Ciba-Geigy Corporation, Summit, New Jersey 07940, USA.
Bruseo
C W
CW
DelGrande
D
D
Jeng
A Y
AY
Savage
P
P
Shetty
S S
SS
D000818:Animals; D001713:Biphenyl Compounds / Q000494:pharmacology*; D001794:Blood Pressure / Q000187:drug effects; D016466:CHO Cells; D006224:Cricetinae; D004151:Dipeptides / Q000494:pharmacology*; D004285:Dogs; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D044023:Receptor, Endothelin B; D012079:Renal Circulation / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects
D001713:Biphenyl Compounds; D004151:Dipeptides; D065128:Endothelin Receptor Antagonists; D016232:Endothelins; C098287:IRL 2500; D044023:Receptor, Endothelin B