Nonpeptide endothelin receptor antagonists. II. Pharmacological characterization of SB 209670.
The pharmacological characterization of SB 209670, a highly potent nonpeptide endothelin ETA/ETB receptor antagonist was performed. SB 209670 produced concentration-dependent, parallel rightward shifts in the ET-1 concentration-response curves in the isolated rat aorta (ETA receptor-mediated vascular contraction). The Kb for inhibition of ETA receptor-mediated contraction by SB 209670 was 0.4 +/- 0.04 nM. Inhibition by SB 209670 was stereoselective as the (+)-antipode of SB 209670 was approximately 575-fold more potent than the (-)-antipode. Relative to other ET receptor antagonists, the potency of SB 209670 for inhibiting ETA receptor-mediated vascular contraction was 45-, 180- and 775-fold more potent than the ETA selective antagonist BQ-123, or the mixed ETA/ETB receptor antagonists bosentan or PD142893, respectively. The pharmacological antagonism produced by SB 209670 was specific for ET-1. SB 209670 inhibited ETB receptors in the isolated rabbit pulmonary artery as demonstrated by concentration-dependent, parallel rightward shifts in either the ET-1 or sarafotoxin S6c (S6c) concentration-response curves. The Kb values for inhibition were 200 +/- 9 and 52 +/- 14 nM for ET-1 and S6c, respectively. In contrast, neither the ETB selective antagonist RES-701 (10 microM) nor BQ-123 (10 microM) inhibited S6c-mediated vasoconstriction. However, PD 142893 (10 microM) and bosentan (10 microM) produced a small rightward shift in the S6c concentration-response curve, each with Kb values of 1.5 to 3.7 microM. In isolated human circumflex coronary arteries, (+/-)-SB 209670 inhibited ET-1 mediated contraction with a Kb value of 7 +/- 3 nM.(ABSTRACT TRUNCATED AT 250 WORDS)
Department of Cardiovascular Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania.
E H
EH
Ohlstein
G R
GR
Beck
S A
SA
Douglas
P
P
Nambi
M A
MA
Lago
J G
JG
Gleason
R R
RR
Ruffolo
G
G
Feuerstein
J D
JD
Elliott
D000328:Adult; D000818:Animals; D004305:Dose-Response Relationship, Drug; D065128:Endothelin Receptor Antagonists; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007189:Indans / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D009842:Oligopeptides / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D013237:Stereoisomerism; D014661:Vasoconstriction
D065128:Endothelin Receptor Antagonists; D007189:Indans; D009842:Oligopeptides; D010456:Peptides, Cyclic; C087551:1H-Indene-2-carboxylic acid, 1-(1,3-benzodioxol-5-yl)-3-(2- (carboxymethoxy)-4-methoxyphenyl)-2,3-dihydro-5-propoxy-, (1S,2R,3S)-; C076213:PD 142893; C072247:cyclo(Trp-Asp-Pro-Val-Leu)