EMS-182874 IS A SELECTIVE, NONPEPTIDE ENDOTHELIN ET(A) RECEPTOR ANTAGONIST

BMS-182874 ylamino)-N-(3,4-dimethyl-5-isoxazolyl)-1-naphalene sulfonam ide] is a recently discovered, low molecular weight, nonpeptide endoth elin (ET) receptor antagonist. EMS-182874 competitively inhibited the binding of [I-125]ET-1 to ET(A) receptors in rat vascular smooth muscl e A10 (VSM-A10) cell membranes (K-i = 61 nM) and in CHO cells stably e xpressing the human ET(A) receptor (K-i = 48 nM), but was a weak inhib itor at ET(B) receptors (K-i > 50 mu M) and non-ET receptors. EMS-1828 74 inhibited ET-1-stimulated inositol phosphate accumulation (K-B = 75 nM) and calcium mobilization (K-B = 140 nM) without suppressing the m aximal responses in VSM-A10 cells. EMS-182874 was a competitive antago nist of force development elicited by stimulation of ET(A), but not ot her, receptors in isolated blood vessels such as the rabbit carotid ar tery (K-B = 520 nM). The apparent discrepancy between efficacy in cell and tissue models was likely related to the high degree of protein bi nding exhibited by EMS-182874. When administered either orally (ED(50) = 30 mu mol/kg) or intravenously (ED(50) = 24 mu mol/kg) to conscious , normotensive rats, EMS-182874 blunted the presser response to exogen ous ET-1. These data demonstrate that EMS-182874 is a competitive, sel ective and orally active ET(A) receptor antagonist that will be useful in understanding the role of ET in normal and disease states.