Binding and function of a potent new thromboxane receptor antagonist, BMS 180,291, in human platelets.
Binding and function of BMS 180,291 ([(+)1S-(1 alpha,2 alpha,3 alpha,4 alpha)]-2-[[3-[4-[(n-pentylamino)carbonyl]-2-oxazolyl]-7- oxabicyclo[2.2.1] hept-2-yl]methyl]benzenepropanoic acid]) in human platelets was examined. Kinetic determination of [3H]BMS 180,291 binding produced ligand-receptor association and dissociation rates of 1.4 x 10(7) +/- 0.2 M-1 x min-1 (n = 5) and 0.04 +/- 0.005 min-1 (n = 5), respectively. The resultant Kd was 3.1 +/- 1.1 nM (n = 5). Saturation binding analysis in platelet membranes was consistent with a single class of [3H]BMS 180,291 binding sites with a Kd of 3.6 +/- 0.19 nM (n = 4) and a binding site maxima (Bmax) of 2099.1 +/- 70.3 fmol/mg of protein (n = 4). Specific [3H]BMS 180,291 binding was inhibited by thromboxane A2/endoperoxide receptor antagonists and agonists with a rank order of potency of: BMS 180,291 > or = SQ 29,548 = I-BOP race 15-(1 alpha,2 beta(5Z), 3 alpha(1E,3S),4 alpha) d7-[3-(3-hydroxy-4-(p-iodophenoxy)-1-butenyl)-7- oxabicyclo[2.2.1]hept-2-yl]5-heptenoic acid) > or = BM 13,505 > or = SQ 30,741 = U 44,609 > U 46,619 >> BM 13,177. Prostaglandin E2 and prostacyclin did not appreciably inhibit the specific binding of [3H]BMS 180,291. BMS 180,291 (10 nM-5 microM) shifted the I-BOP-induced platelet shape change curve to the right in a parallel manner without reduction of the maximal response (KB = 13 +/- 3.5 nM; pA2 = 8 +/- 0.2; slope = -1.0 +/- 0.05), whereas 30 nM drug decreased the maximal I-BOP-induced platelet aggregation.(ABSTRACT TRUNCATED AT 250 WORDS)
Webb
M L
ML
Department of Cardiovascular Biochemistry, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, New Jersey.
Liu
E C
EC
Monshizadegan
H
H
Hedberg
A
A
Misra
R N
RN
Goldenberg
H
H
Harris
D N
DN
D001713:Biphenyl Compounds / Q000378:metabolism / Q000494:pharmacology; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism*; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology; D019086:Bridged Bicyclo Compounds, Heterocyclic; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology; D006538:Heptanoic Acids / Q000378:metabolism / Q000494:pharmacology; D006801:Humans; D006834:Hydrazines / Q000378:metabolism / Q000494:pharmacology; D066298:In Vitro Techniques; D007700:Kinetics; D010080:Oxazoles / Q000378:metabolism* / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects; D011422:Propionates / Q000378:metabolism* / Q000494:pharmacology; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors*
D001713:Biphenyl Compounds; D001643:Bridged Bicyclo Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D005231:Fatty Acids, Unsaturated; D006538:Heptanoic Acids; D006834:Hydrazines; D010080:Oxazoles; D011422:Propionates; D017482:Receptors, Thromboxane; C061750:7-(3-(3-hydroxy-4-(4'-iodophenoxy)-1-butenyl)-7-oxabicyclo(2.2.1)heptan-2-yl)-5-heptenoic acid; C045749:SQ 29548; C078904:ifetroban; C060013:vapiprost