NONPEPTIDE ENDOTHELIN RECEPTOR ANTAGONISTS - XI - PHARMACOLOGICAL CHARACTERIZATION OF SB-234551, A HIGH-AFFINITY AND SELECTIVE NONPEPTIDE ETA-RECEPTOR ANTAGONIST

The present study describes the pharmacological profile of -[2-[(2-car boxyphenyl)methoxy]-4-methoxy-phenyl]-1 l]methlene]-6-methoxy-1,3-benz odioxole-5-propanoic acid) (SB 234551), a high-affinity, nonpeptide en dothelin type A (ETA)-selective receptor antagonist. In human cloned E TA and endothelin type B (ETB) receptors, SE 234551 produced a concent ration-dependent displacement of [I-125]-endothelin-1 with K-l values of 0.13 and 500 nM, respectively. SE 234551 elicited concentration-dep endent, rightward competitive shifts in the endothelin-l concentration -response curves in isolated rat aorta and isolated human pulmonary ar tery (ETA receptor-mediated vascular contraction) with K-l values of 1 .9 and 1.0 nM, respectively. SE 234551 antagonized ET, receptor-mediat ed vasoconstriction in the isolated rabbit pulmonary artery, as demons trated by concentration-dependent, rightward shifts in the sarafotoxin S6c concentration-response curves (K-b = 555 nM). SE 234551 produced weak functional inhibition of sarafotoxin S6c-mediated endothelium-dep endent relaxation (IC50 = 7 mu M). SE 234551 (10 mu M) had no signific ant effect against contraction produced by several other vasoactive ag ents and did not significantly influence radioligand binding to a numb er of diverse receptors. SE 234551 (0.1-1.0 mg/kg i.v.) dose-dependent ly inhibited the presser response to exogenous endothelin-l in conscio us rats. In vivo pharmacokinetic analysis in the rat demonstrated that SE 234551 was rapidly absorbed from the GI tract with a bioavailabili ty of 30%. SE 234551 had a plasma half-life of 125 min and a systemic clearance of 25.0 ml/min/kg. The present study demonstrates that SE 23 4551 is an antagonist with high affinity for the ET, receptor, while s paring the ET, receptor. SE 234551 is a new pharmacological tool that should assist in the elucidation of the role of endothelin in pathophy siology.