Characterization of Thromboxane A2/Prostaglandin H2 Receptors in Porcine Coronary Artery -The Inhibitory Effect of a Novel Dibenzoxepin Derivative, KW-3635

Abstract

SummaryWe characterized the thromboxane A2/prostaglandin H2 receptors in porcine coronary artery. The binding of [3H]SQ 29,548, a thromboxane A2 antagonist, to coronary arterial membranes was saturable and displaceable. Scatchard analysis of equilibrium binding showed a single class of high affinity binding sites with a dissociation constant of 18.5 ±1.0 nM and the maximum binding of 80.7 ± 5.2 fmol/mg protein. [3H]SQ 29,548 binding was concentration-dependently inhibited by thromboxane A2 antagonists such as SQ 29,548, BM13505 and BM13177 or the thromboxane A2 agonists such as U46619 and U44069. KW-3635, a novel dibenzoxepin derivative, concentration-dependently inhibited the [3H]SQ 29,548 binding to thromboxane A2/prosta-glandin H2 receptors in coronary artery with an inhibition constant of 6.0 ± 0.69 nM (mean ± S.E.M.).

Design, synthesis and biological evaluation of a sulfonylcyanoguanidine as thromboxane A2 receptor antagonist and thromboxane synthase inhibitor

“…A wide variety of TXA 2 receptor antagonists have been synthesized. These antagonists (Figure 1) are distributed into the sulfonamide derivatives from which sulotroban (2) is the lead compound (Gresele et al 1984), into the potent ω-alkylcarboxylic compounds with SQ-29548 (3) (Ogletree et al 1985) and seratrodast (4) (Kurokawa et al 1994) as prototypes, and into a class of various tricyclic molecules (Hall et al 1987 ;Jessup et al 1988 ;Ford-Hutchinson et al 1989 ;Miki & Ishii 1992 ;Theis et al 1992 ;Romstedt et al 1993 ;Takeuchi et al 1998). In 1992, torasemide (5, Figure 2), a diuretic sulfonylurea acting by inhibiting the Na + K + 2Cl − co-transporter (Friedel & Buckley 1991), was described as a poor TXA 2 receptor antagonist able to relax the canine coronary artery precontracted with TXA 2 (Uchida et al 1992).…”