Antiplatelet and Antithrombotic Activity of SL65.0472, a Mixed 5-HT1B/5-HT2A Receptor Antagonist

Christopher N. Berry; Janine Lorrain; Sylvette Lochot; Monique Delahaye; Alain Lalé; Pierre Savi; Irène Lechaire; Patrice Ferrari; André Bernat; Paul Schaeffer; Philippe Janiak; Nicole Duval; Alain Grosset; Jean-Marc Herbert; Stephen E. O’Connor

doi:10.1055/s-0037-1615615

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2001; 85(03): 521-528
DOI: 10.1055/s-0037-1615615

Review Article

Schattauer GmbH

Antiplatelet and Antithrombotic Activity of SL65.0472, a Mixed 5-HT_1B/5-HT_2A Receptor Antagonist

Christopher N. Berry

¹Cardiovascular/Thrombosis Department, Sanofi~Synthélabo, Chilly Mazarin, and Toulouse, France

,

Janine Lorrain

¹Cardiovascular/Thrombosis Department, Sanofi~Synthélabo, Chilly Mazarin, and Toulouse, France

,

Sylvette Lochot

¹Cardiovascular/Thrombosis Department, Sanofi~Synthélabo, Chilly Mazarin, and Toulouse, France

,

Monique Delahaye

¹Cardiovascular/Thrombosis Department, Sanofi~Synthélabo, Chilly Mazarin, and Toulouse, France

,

Alain Lalé

¹Cardiovascular/Thrombosis Department, Sanofi~Synthélabo, Chilly Mazarin, and Toulouse, France

,

Pierre Savi

¹Cardiovascular/Thrombosis Department, Sanofi~Synthélabo, Chilly Mazarin, and Toulouse, France

,

Irène Lechaire

¹Cardiovascular/Thrombosis Department, Sanofi~Synthélabo, Chilly Mazarin, and Toulouse, France

,

Patrice Ferrari

¹Cardiovascular/Thrombosis Department, Sanofi~Synthélabo, Chilly Mazarin, and Toulouse, France

,

André Bernat

¹Cardiovascular/Thrombosis Department, Sanofi~Synthélabo, Chilly Mazarin, and Toulouse, France

,

Paul Schaeffer

¹Cardiovascular/Thrombosis Department, Sanofi~Synthélabo, Chilly Mazarin, and Toulouse, France

,

Philippe Janiak

¹Cardiovascular/Thrombosis Department, Sanofi~Synthélabo, Chilly Mazarin, and Toulouse, France

,

Nicole Duval

¹Cardiovascular/Thrombosis Department, Sanofi~Synthélabo, Chilly Mazarin, and Toulouse, France

,

Alain Grosset

¹Cardiovascular/Thrombosis Department, Sanofi~Synthélabo, Chilly Mazarin, and Toulouse, France

,

Jean-Marc Herbert

¹Cardiovascular/Thrombosis Department, Sanofi~Synthélabo, Chilly Mazarin, and Toulouse, France

,

Stephen E. O’Connor

¹Cardiovascular/Thrombosis Department, Sanofi~Synthélabo, Chilly Mazarin, and Toulouse, France

› Institutsangaben

Abstract

Summary

The antiplatelet and antithrombotic activity of SL65.0472 (7-fluoro-2-oxo-4-[2-[4-(thieno [3,2-c]pyrin-4-yl) piperazin-1-yl]ethyl]-1,2-dihydroquinoline-acetamide), a mixed 5-HT_1B/5-HT_2A receptor antagonist was investigated on 5HT-induced human platelet activation in vitro, and in rat, rabbit and canine platelet dependent thrombosis models. SL65.0472 inhibited 5-HT-induced platelet shape change in the presence of EDTA (IC₅₀ values = 35, 69 and 225 nM in rabbit, rat and human platelet rich plasma (PRP)), and also inhibited aggregation induced in human PRP by 3-5 μM 5-HT + threshold concentrations of ADP (0.5-1 M) or collagen (0.3 g/ml) with mean IC₅₀ values of 49 ± 13 and 48 ± 6 nM respectively. SL65.0472 inhibited thrombus formation when given both intravenously 5 min and orally 2 h prior to assembly of an arterio-venous (A-V) shunt in rats as from 0.1 and 0.3 mg/kg respectively. It was active in a rabbit A-V shunt model with significant decreases in thrombus weight as from 0.1 mg/kg i. v. and at 10 mg/kg p. o. The delay to occlusion in an electric current-induced rabbit femoral artery thrombosis model was increased by 251% (p <0.05) after 20 mg/kg p. o. SL65.0472 (30 μg/kg i. v.) virtually abolished coronary cyclic flow variations (7.2 ± 1.0/h to 0.6 ± 0.6/h, p <0.05) and increased minimum coronary blood flow (1.2 ± 0.8 ml/ min to 31.8 ± 8.4 ml/min, p <0.05) in a coronary artery thrombosis model in the anaesthetised dog. Finally, SL65.0472 significantly increased the amount of blood lost after rat tail transection at 3 mg/kg p. o. Thus the anti-5-HT_2A component of SL65.0472 is reflected by its ability to inhibit 5-HT-induced platelet activation, and platelet-rich thrombus formation.

Keywords

SL65.0472 - 5-hydroxytryptamine - platelet activation - experimental arterial thrombosis

Volltext

Referenzen

References
1 Patrono S, Coller BS, Dalen JE, Fuster V, Gent M, Harker LA, Hirsh J, Roth G. Platelet-active drugs. The relationships among dose, effectiveness, and side effects. Chest 1998; 114: 470S-88S.
2 CAPRIE Steering Committee.. A randomised, blinded trial of clopidogrel versus aspirin in patients at risk of ischemic events (CAPRIE). Lancet 1996; 348: 1329-39.
3 Herbert JM, Savi P, Maffrand JP. Biochemical and pharmacological properties of clopidogrel: a new ADP receptor antagonist. Eur Heart J. Suppl 1999; 1: A31-A40.
4 The EPIC investigators.. Use of a monoclonal antibody directed against the platelet glycoprotein IIb/IIIa receptor in high risk coronary angioplasty. N Engl J Med 1994; 330: 956-61.
5 Glennon R, Dukat M. Novel serotoninergic agents: 5HT₂ – update 1997. Serotonin ID. Research Alert 1997; 2: 107-13.
6 Scrutton MC, Thompson NT. Agonists and receptors: serotonin. In “Platelet responses and metabolism”. Volume II H. Holmsen. Ed. CRC Press; Boca Raton NC: 1986. pp. 57-68.
7 De Clerck F, Xhonneux B, Leysen J, Janssen PAJ. Evidence for functional 5-HT₂ receptor sites on human blood platelets. Biochem Pharmacol 1984; 8: 2807-11.
8 Da Prada M, Picotti GB. Content and subcellular localisation of catechola-mines and 5-hydroxytryptamine content and aggregation of rabbit platelets. Br J Pharmacol 1979; 65: 653-62.
9 De Clerck F, David JL, Janssen PAJ. Inhibition of 5-hydroxytryptamine-induced and -amplified human platelet aggregation by ketanserin (R 41 468), a selective 5-HT₂ receptor antagonist. Agents and Actions 1982; 12: 388-97.
10 De Clerck F, Xhonneux B. Effects of ketanserin, a selective 5-HT₂ serotonergic antagonist, on the secondary recruitment of human platelets in vitro. Agents and Actions 1985; 17: 516-26.
11 Bush LR. Effects of the serotonin antagonists, cyproheptadine, ketanserin and mianserin, on cyclic flow reductions in stenosed canine coronary arteries. J Pharm Exp Ther 1987; 240: 674-82.
12 Torr S, Noble MIM, Folts JD. Inhibition of acute platelet thrombosis formation in stenosed canine coronary arteries by specific serotonin 5HT₂ antagonist ritanserin. Cardiovasc Res 1990; 24: 465-70.
13 Hara H, Kitajima A, Shimada H, Tamao Y. Antithrombotic effect of MCI-9042, a new antiplatelet agent on experimental thrombosis model. Thromb Haemost 1991; 66: 484-8.
14 Wilson HC, Coffman W, Killam AL, Cohen ML. LY53857, a 5HT₂ receptor antagonist, delays occlusion and inhibits platelet aggregation in a rabbit model of carotid artery occlusion. Thromb Haemost 1991; 66: 355-60.
15 Cohen ML, Robertson DW, Bloomquist WE, Wilson HC. LY215840, a potent 5-hydroxytryptamine (5-HT)₂ receptor antagonist, blocks vascular and platelet 5-HT₂ receptors and delays occlusion in a rabbit model of thrombosis. J Pharm Exp Ther 1992; 261: 202-8.
16 Tanaka T, Morishima Y, Watanabe K, Shibutani T, Yasuoka M, Shibano T. Combined effect of the 5-HT₂ receptor antagonist DV-7028 and aspirin or heparin on coronary cyclic flow reductions in dogs. Cardiovasc Res 1993; 27: 1374-9.
17 Herbert JM, Bernat A, Barthelemy G, Dol F, Rinaldi M. Antithrombotic activity of SR 46349, a novel, potent and selective 5-HT₂ receptor antagonist. Thromb Haemost 1993; 69: 262-7.
18 Toda N, Okamura T. Comparison of the response to 5-carboxamidotrypta-mine and serotonin in isolated human, monkey and dog coronary arteries. J Pharm Exp Ther 1990; 253: 676-82.
19 Golino P, Piiscione F, Willerson JT, Capelli-Bigazzi M, Focaccia A, Villari B, Indolfi C, Russolillo E, Condorelli M, Chiariello M. Divergent effects of serotonin on coronary-artery dimensions and blood flow in patients with coronary atherosclerosis and control patients. N Engl J Med 1991; 324: 641-8.
20 Vanhoutte PM. Platelet-derived serotonin, the endothelium, and cardiovascular disease. J Cardiovasc Pharmacol 1991; 17 (Suppl. 05) S6-S12.
21 MacLennan SJ, Martin GR. Effect of the thromboxane A₂ -mimetic U46619 on 5HT₁-like and 5-HT₂ receptor-mediated contraction of the rabbit isolated femoral artery. Br J Pharmacol 1992; 107: 418-21.
22 Kaumann AJ, Frenken M, Posival H, Brown AM. Variable participation of 5-HT₁-like receptors and 5-HT₂ receptors in serotonin-induced contraction of human isolated coronary arteries. 5-HT₁-like receptors resemble cloned 5-HT_1Dβ receptors. Circulation 1994; 90: 1141-53.
23 Choppin A, O’Connor SE. Presence of vasoconstrictor 5HT₁-like receptors revealed by precontraction of rabbit isolated mesenteric artery. Br J Pharmacol 1995; 114: 309-14.
24 Sgard F, Faure C, Graham D. Evidence for 5-HT_1Dβ but not 5-HT_1Dβ receptor subtype expression in canine large coronary arteries and saphenous vein. Cardiovasc res 1996; 31: 793-9.
25 O’Connor SE, Grosset A, Duval N, Drieu La Rochelle C, Gautier E, Bidouard JP, Janiak P. 5-HT_1B- and 5-HT_2A-receptor antagonist properties of SL65.0472 in vivo. Br J Pharmacol 2000; 129: 58P.
26 Berry CN, Lorrain J, Lochot S, Delahaye M, Lalé A, Savi P, Lechaire J, Bernat A, Schaeffer P, Herbert JM, O’Connor SE. Antiplatelet and oral antithrombotic activity of SL 65.0472. Br J Pharmacol 2000; 129: 57P.
27 Born GVR, Cross MJ. The aggregation of blood platelets. J Physiol 1963; 168: 178-95.
28 Folts JD. An in vivo model of experimental arterial stenosis, intimal damage and periodic thrombosis. Circulation 1991; 83 Suppl. IV 3-14.
29 Gaddum JH. Introductory address, Part 1. Biological aspects: the antagonism of drugs. Trans Faraday Soc 1943; 39: 323-32.
30 Packham MA, Kinlough-Rathbone RL, Mustard JF. Thromboxane A₂ causes feedback amplification involving extensive thromboxane A₂ formation upon close contact of human platelets in media with a low concentration of ionized calcium. Blood 1987; 70: 647-51.
31 Packham MA, Bryant NL, Guccione MA, Kinlough-Rathbone RL, Mustard JF. Effect of concentration of Ca²⁺ in the suspending medium on the responses of human and rabbit platelets to aggregating agents. Thromb Haemost 1987; 62: 968-76.
32 Herbert JM, Frehel D, Bernat A, Badorc A, Savi P, Delebassee D, Kieffer G, Defreyn G, Maffrand JP. Clopidogrel hydrogensulfate. Drugs Future 1993; 18: 107-12.
33 Herbert JM, Dol F, Bernat A, Falotico R, Lalé A, Savi P. The antiaggregating and antithrombotic activity of clopidogrel is potentiated by aspirin in several experimental models in the rabbit. Thromb Haemost 1998; 80: 512-8.
34 Peters RF, Lees CM, Mitchell KA, Tweed MF, Talbot MD, Wallis RB. The characterisation of thrombus development in an improved model of arteriovenous shunt thrombosis in the rat and the effects of recombinant desulphatohirudin (CGP 39393), heparin, and iloprost. Thromb Haemost 1991; 65: 268-74.
35 Folts JD, Crowell EB, Rowe GG. Platelet aggregation in partially obstructed vessels and its elimination with aspirin. Circulation 1976; 54: 365-70.
36 Golino P, Buja LM, Ashton JH, Kulkarni P, Taylor A, Willerson JT. Effect of thromboxane and serotonin receptor antagonists on intracoronary platelet deposition in dogs with experimentally stenosed coronary arteries. Circulation 1988; 78: 701-11.
37 Parsons AA, Stutchbury C, Raval P, Kaumann AJ. Sumatriptan contracts large coronary arteries of beagle dogs through 5-HT-like receptors. Naunyn Schmiedeberg’s Arch Pharmacol 1992; 346: 592-6.
38 Cushing DJ, Cohen ML. Comparison of the serotonin receptors that mediate smooth muscle contraction in canine and porcine coronary artery. J Pharmacol Exp Ther 1992; 261: 856-62.
39 Ashton JH, Benedict CR, Fitzgerald C. Serotonin as a mediator of cyclical flow variations in stenosed canine coronary arteries. Circulation 1986; 73: 572-8.
40 Beaughard M, Brasset M, John G, Massingham R. Failure of calcium channel blockade to reduce platelet-mediated cyclic flow variations in dogs with coronary stenosis and endothelial injury. J Cardiovasc Pharmacol 1995; 26: 577-83.
41 Saxena PR, Villalón CM. Cardiovascular effects of serotonin agonists and antagonists. J Cardiovasc Pharmacol 1990; 15 (Suppl. 07) S17-34.