J-104132 [(+)-(5S,6R, 7R)-2-butyl-7-[2-((2S)-2-carboxypropyl)-4-methoxyphenyl]-5-(3, 4-methylenedioxyphenyl)cyclopenteno[1,2-b]pyridine-6-carboxylic; also referred to as L-753,037] is a potent, selective inhibitor of ETA and ETB endothelin (ET) receptors (e.g., Ki: cloned human ETA = 0.034 nM; cloned human ETB = 0.104 nM). In both ligand-binding and isolated tissue preparation protocols, the inhibition of ET receptors with J-104132 is reversible and competitive. In vitro, J-104132 is a potent antagonist of ET-1-induced accumulation of [3H]inositol phosphates in Chinese hamster ovary cells stably expressing cloned human ETA receptors (IC50 = 0.059 nM), ET-1-induced contractions in rabbit iliac artery (pA2 = 9.70) and of BQ-3020-induced contractions in pulmonary artery (pA2 = 10.14). J-104132 is selective for ET receptors because it had no effect on contractions elicited by norepinephrine or KCl in the vascular preparations. The in vivo potency of J-104132 was assessed using challenges with exogenous ET-1. In conscious mice, 5 nmol/kg i.v. ET-1 causes death. Pretreatment with J-104132 prevents the lethal response to ET-1 when administered i.v. (ED50 = 0.045 mg/kg) or p.o. in fed animals (ED50 = 0.35 mg/kg). In conscious, normotensive rats, pressor responses to 0.5 nmol/kg i.v. ET-1 are inhibited by J-104132 after i.v. (0.1 mg/kg) or p.o. (1 mg/kg) administration. In anesthetized dogs, ET-1 was administered directly into the renal artery or brachial artery to generate dose-response (blood flow) curves, and the inhibitory potency of J-104132 (i.v. infusion) was quantified. J-104132 produced greater than 10-fold shifts in the ET-1 dose-response curves at 0.03 mg/kg/h (renal) and 0.3 mg/kg/h (brachial). Oral bioavailability of J-104132 in rats was approximately 40%. These studies indicate that J-104132 is a selective, potent, orally active antagonist of both ETA and ETB receptors and is an excellent pharmacological tool to explore the therapeutic use of a mixed ETA/ETB receptor antagonist.