title: BMS-182874 is a selective, nonpeptide endothelin ETA receptor antagonist.
abstract: BMS-182874 [5-(dimethylamino)-N-(3,4-dimethyl-5-isoxazolyl)-1-naphthalene sulfonamide] is a recently discovered, low molecular weight, nonpeptide endothelin (ET) receptor antagonist. BMS-182874 competitively inhibited the binding of [125I]ET-1 to ETA receptors in rat vascular smooth muscle A10 (VSM-A10) cell membranes (Ki = 61 nM) and in CHO cells stably expressing the human ETA receptor (Ki = 48 nM), but was a weak inhibitor at ETB receptors (Ki > 50 microM) and non-ET receptors. BMS-182874 inhibited ET-1-stimulated inositol phosphate accumulation (KB = 75 nM) and calcium mobilization (KB = 140 nM) without suppressing the maximal responses in VSM-A10 cells. BMS-182874 was a competitive antagonist of force development elicited by stimulation of ETA, but not other, receptors in isolated blood vessels such as the rabbit carotid artery (KB = 520 nM). The apparent discrepancy between efficacy in cell and tissue models was likely related to the high degree of protein binding exhibited by BMS-182874. When administered either orally (ED50 = 30 mumol/kg) or intravenously (ED50 = 24 mumol/kg) to conscious, normotensive rats, BMS-182874 blunted the pressor response to exogenous ET-1. These data demonstrate that BMS-182874 is a competitive, selective and orally active ETA receptor antagonist that will be useful in understanding the role of ET in normal and disease states.
authors.affiliation: Department of Cardiovascular Biochemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey.
authors.forename: M L
authors.initials: ML
authors.lastname: Webb
authors.forename: J E
authors.initials: JE
authors.lastname: Bird
authors.forename: E C
authors.initials: EC
authors.lastname: Liu
authors.forename: P M
authors.initials: PM
authors.lastname: Rose
authors.forename: R
authors.initials: R
authors.lastname: Serafino
authors.forename: P D
authors.initials: PD
authors.lastname: Stein
authors.forename: S
authors.initials: S
authors.lastname: Moreland
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D001792:Blood Platelets / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002531:Cerebellum / Q000378:metabolism; D003619:Dansyl Compounds / Q000378:metabolism / Q000494:pharmacology*; D004285:Dogs; D065128:Endothelin Receptor Antagonists; D016232:Endothelins / Q000378:metabolism*; D005920:Glomerular Mesangium / Q000378:metabolism; D006801:Humans; D008168:Lung / Q000378:metabolism; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D010456:Peptides, Cyclic / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin / Q000378:metabolism; D013552:Swine
chemical_list: D003619:Dansyl Compounds; D065128:Endothelin Receptor Antagonists; D016232:Endothelins; D010456:Peptides, Cyclic; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin; C085754:5-(dimethylamino)-N-(3,4-dimethyl-5-isoxazolyl)-1-naphthalenesulfonamide; C072247:cyclo(Trp-Asp-Pro-Val-Leu); D002118:Calcium