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Stable Derivatives of Thromboxane A2 with Differential Effects on Platelets

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Stable Derivatives of Thromboxane A2 with Differential Effects on Platelets Proc. Natl. Acad. Sci. USA Vol. 86, pp. 5600-5604, July 1989 Medical Sciences Difluorothromboxane A2 and stereoisomers: Stable derivatives of thromboxane A2 with differential effects on platelets and blood vessels (receptors/contraction/aggregation/prostaglandins/10,10-difluorothromboxane A2 and analogues) THOMAS A. MORINELLI*, ANSELM K. OKWU*, DALE E. MAIS*, PERRY V. HALUSHKA*t, VARGHESE JOHNt, CHIEN-KUANG CHENt, AND JOSEF FRIEDt Departments of *Cell and Molecular Pharmacology and Experimental Therapeutics and of tMedicine, Medical University of South Carolina, Charleston, SC 29425; and tDepartment of Chemistry, The University of Chicago, Chicago, IL 60637 Contributed by JosefFried, April 13, 1989 ABSTRACT The present study reports on the selective this analogue is an antagonist (13). Other studies, also using effects on human platelets and canine saphenous veins of four different species, have shown differences in receptors in the stable difluorinated analogues and thromboxane A2 (TXA2), in two cell types (14, 15). Because different species were used which the characteristic 2,6-dioxa[3.1.1]bicycloheptane struc- as the source of platelets and blood vessels, these differences ture of TXA2 has been retained. The four compounds differ in may be species-selective rather than represent actual differ- their stereochemistry of the 5,6 double bond and/or the ences in the receptors. 15-hydroxyl group. Only 10,10-difluoro-TXA2 (compound I) Recent studies, however, have provided stronger evidence with the natural stereochemistry of TXA2 was an agonist in for different TXA2/PGH2 receptors in platelets and in blood both platelets and canine saphenous veins (EC50 = 36 ± 3.6 nM vessels (12, 16, 17). The platelet and vascular receptors also and 3.7 ± 0.8 nM, respectively). (15R)-10,10-Difluoro-TXA2 differ in their steric requirements for the orientation of the (compound II), (5E)-10,10-difluoro-TXA2 (compound IM), and 15-hydroxyl group (17). In saphenous veins orientation ofthe (5E,15R)-10,10-difluoro-TXA2 (compound IV) were antago- 15-hydroxyl group influenced the potency of the compounds nists of platelet aggregation stimulated by compound I (Kd = as antagonists in the vessels, whereas in platelets the orien- 98 ± 46 nM, 140 ± 42 nM, and 1450 ± 350 nM, respectively). tation had no influence. The platelet receptor has been However, compounds 11,1, and IV stimulated contraction of designated the (TXA2/PGH2)a receptor, a for aggregation, canine saphenous veins (EC50 = 36 ± 4.4 nM, 31 ± 6.8 nM, and and the vascular receptor (TXA2/PGH2), r for tone (12, 16, 321 ± 50 nM, respectively). All four compounds could displace 17). the TXA2/prostaglandin H2 antagonist 9,11-dimethylmeth- Most compounds used in these studies possessed the ano-11,12-methano-16-(3-'251-4-hydroxyphenyl)-13,14-dihy- [2.2.1]bicycloheptane skeleton of PGH2; less attention had dro-13-aza-15a13-w-tetranor-TXA2 from its platelet receptor been paid to analogues of TXA2, which possess the (Kd values = 100 ± 30 nM, compound I; 280 ± 60 nM, [3.1.1]bicycloheptane system. In both structural types in- compound II; 230 ± 70 nM, compound HI; and 1410 ± 1020 creased stability was imparted to the molecules by substitu- nM, compound IV). These results support the existence of two tion of one or both of the oxygen atoms by carbon, sulfur, or subtypes of TXA2/prostaglandin H2 receptors and emphasize nitrogen. However, these systems still represent significant the importance of the stereochemical requirements of these structural changes compared with TXA2 or PGH2. Indeed, TXA2 analogues for interaction with these receptors. These some of these analogues do not mimic the actions ofTXA2 in stable fluorinated TXA2 analogues should prove useful tools for platelets (13) and blood vessels. The current studies report on the further characterization of these and other TXA2/pros- the selective effects on human platelets and canine saphenous taglandin H2 receptors. veins of a difluoro analogue of TXA2 and three of its stereo- isomers in which the 2,6-dioxabicyclo structure of TXA2 has Thromboxane A2 (TXA2), and prostaglandin H2 (PGH2) been retained except for the substitution of two hydrogen cause aggregation of platelets and constriction of vascular atoms by fluorine (18). smooth muscle (1-4) by means of cell-surface receptors. To study the specific events accompanying the interaction of these autacoids with their receptors, it is necessary to use MATERIALS AND METHODS stable analogues because both TXA2 and PGH2 are unstable, The syntheses of the four difluorinated TXA2 derivatives, their half-lives under physiological conditions being 30 sec compounds I-IV (Fig. 1), used in this study are described and 5 min, respectively. For these reasons many compounds elsewhere (18). 9,11-Dimethy-lmethano-11,12-methano- have been synthesized that are related in structure to both 16-(3-iodo-4-hydroxyphenyl)-13 ,14-dihydro-13-aza-15a,B- PGH2 and TXA2 and that act as either agonists or antagonists w-tetranor-TXA2 (I-PTA-OH) and [1251]PTA-OH were syn- for TXA2/PGH2 receptors on platelets and vascular smooth thesized as described (11). U-46619 was a gift from Upjohn. muscle (5-12). Platelet Aggregation. Blood was drawn via venipuncture Studies ofthese analogues have provided evidence that the from normal human volunteers, who had not taken any TXA2/PGH2 receptors on vascular smooth muscle differ from those of platelets. For example, a carbocyclic analogue Abbreviations: PGH2, prostaglandin H2; TXA2, thromboxane A2; of TXA2 [2,3(Z),3a-(lE,3R)-3-(3-hydroxy(1-octenyl)-bicyclo- CTA2, 2,B(Z),3a-(lE,3R)-3-(3-hydroxy(1-octenyl)-bicyclo[3.1.1I- [3.1.1]hept-2-yl-5-heptenoic acid; CTA2] has been shown to hept-2-yl-5-heptenoic acid; I-PTA-OH, 9,11-dimethylmethano- constrict cat coronary arteries, whereas in human platelets 11,12-methano-16-(3-iodo-4-hydroxyphenyl)-13,14-dihydro-13-aza- 15a13-co-tetranor-TXA2; U-46619, (15S)-hydroxy-lla,9a-(epoxy- methano)prosta-(5Z,13E)-dienoic acid; SQ 29548, -{(lS)-[la,2.8- The publication costs of this article were defrayed in part by page charge (5Z),3p,4a]}-7-[3-({2-[(phenylamino)carbonyl]hydrazino}methyl)- payment. This article must therefore be hereby marked "advertisement" 7-oxabicyclo[2.2.1]hept-2-yl]-5-heptenoic acid; STA2, 9,11-epithio- in accordance with 18 U.S.C. §1734 solely to indicate this fact. 11,12-methano-TXA2- 5600 Downloaded by guest on September 25, 2021 Medical Sciences: Morinelli et al. Proc. Natl. Acad. Sci. USA 86 (1989) 5601 F F * 'C."b F . | F F.0e ~~~~~~~COOH 00 0 OH OH II F ...' s COCH F ,.0 | 09 OH III IV . I COOH 0 0. OH OH U46619 FIG. 1. Structure of difluoro-TXA2 and three of its stereoisomers used in this study, along with the structures ofTXA2 and U-46619, a stable PGH2 analogue. Compound I, 10,10-difluoro-TXA2; compound II, (15R)-10,10-difluoro-TXA2; compound III, (5E)-10,10-difluoro-TXA2; and compound IV, (5E,15R)-10,10-difluoro-TXA2. medication for at least 10 days, into syringes containing 10 min. Incubation medium was 50 mM Tris/100 mM NaCl AuM indomethacin/5 mM EDTA (final concentrations). In- buffer containing -0.1 nM (-5 x 104 cpm) [125I]PTA-OH per formed consent was obtained from all subjects; this study was tube. The reaction was terminated by adding 4 ml of the approved by the Medical University of South Carolina In- ice-cold Tris/NaCl buffer at pH 7.4, followed by rapid stitutional Review Board for Human Research. Washed filtration through Whatman GF/C glass fiber filters. Filters platelets, prepared as described (12), were suspended in a 50 were washed three more times with 4 ml ofthe ice-cold buffer mM Tris/100 mM NaCl, pH 7.4, buffer containing 5 mM (11). The IC50 values obtained from log-logit transformation glucose. Before aggregation 250 /M CaCl was added to the of the competition binding data were defined as the concen- platelet suspension. Platelets were aggregated in a Chronolog trations of ligand required to produce a 50% displacement of model 300 aggregometer by using published methods (17). specifically bound [1251]PTA-OH from its binding site. The The washed platelets (450 ILI, 5.0 x 188 platelets per ml) were IC50 value was used to determine the Kd by using the added to individual glass cuvettes and preincubated for 1 min Cheng-Prusoff equation (20). Nonspecific binding was de- at 370C. Then difluoro-TXA2 (compound I) or the stable fined as that amount of radioactivity remaining in the pres- TXA2/PGH2 mimetic U-46619 (6) was added (final concen- ence of 750 nM I-PTA-OH (11). trations varied between 5 nM and 5 PM), and the aggregation Saphenous Veins. Medial saphenous veins were dissected response was recorded. Concentration-response curves from pentobarbital-anesthetized mongrel dogs (30 mg/kg) were constructed for U-46619 and difluoro-TXA2 (compound and placed into ice-cold Krebs-Henseleit bicarbonate buffer I), and the EC50 values were calculated directly from log-logit (118 mM NaCI/5.4 mM KCI/1.0 mM MgSO4/2.5 mM CaCl2/ transformations of the data. The EC50 value was defined as 1.1 mM NaH2PO4/25 mM NaHCO3/10 mM D-glucose/10 the concentration required to produce 50o of the maximum ,uM indomethacin). After removal of surrounding fascia the aggregation occurring 1 min after addition of the aggregating vein was cut into rings (5-6 mm long) and attached to an agent. isometric force-displacement transducer (Grass). The tissues In studies using the difluoro-TXA2 isomers, compounds II, were maintained at 2 g of resting tension and allowed to III, and IV, to inhibit difluoro-TXA2-stimulated platelet stabilize for =1 hr at 37°C in Krebs-Henseleit buffer (95% aggregation the following method was used.
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