PDF herunterladen
Thromb Haemost 1993; 69(03): 262-267
DOI: 10.1055/s-0038-1651592
Original Article
Platelets
Schattauer GmbH Stuttgart

Antithrombotic Activity of SR 46349, a Novel, Potent and Selective 5-HT2 Receptor Antagonist

J M Herbert
Sanofi Recherche, Toulouse, France
,
A Bernat
Sanofi Recherche, Toulouse, France
,
G Barthelemy
Sanofi Recherche, Toulouse, France
,
F Dol
Sanofi Recherche, Toulouse, France
,
M Rinaldi
1   Sanofi Recherche, Montpellier, France
› Institutsangaben
Weitere Informationen

Publikationsverlauf

Received 04. Juni 1992

Accepted after revision 26. Oktober 1992

Publikationsdatum:
05. Juli 2018 (online)

Auch verfügbar auf
  als PDF herunterladen  Lizenzen und Reprints

Summary

SR 46349 (trans-4-[(3Z)3-(2-dimethylaminoethyl)oxyimino-3(2-fluorophenyl)propen-1-yl] phenol, hemifumarate) is the first member of a newly-developed 5-HT2 antagonist series. SR 46349 potently inhibited serotonin-induced aggregation of rabbit and human platelets (IC50 = 1 and 3.9 nM respectively) but had no effect on the action of other platelet aggregating agents. SR 46349 was 118 and 25 times more potent than ketanserin against 5-HT + epinephrine-induced aggregation of rabbit and human platelets respectively.

A single per os administration of SR 46349 (1 mg/kg) resulted in a strong inhibition of 5-HT + epinephrine-induced platelet aggregation in the rabbit as measured ex vivo (67% inhibition, 6 h after the administration). Intravenous or oral administration of SR 46346 inhibited in a dose-dependent manner venous thrombosis induced by ligature of the jugular vein of rabbits whose blood was made hypercoagulable by i.v. administration of tissue thromboplastin. The doses of SR 46349 which inhibited 50% of thrombus formation were 1.5 ± 0.8 mg/kg and 17 ± 0.5 mg/kg after i.v. or oral administration respectively. When given i.v. to rabbits, SR 46349 exhibited a dose-dependent antithrombotic effect in an arterio-venous shunt model. Significant increase of the bleeding time was observed after the i.v. administration of 5 mg/kg of SR 46349 (3-fold increase). In dogs, SR 46349 inhibited cyclic coronary artery blood flow variations, complete abolition of CFVs being achieved after the i.v. administration of 0.5 mg/kg.

In conclusion, SR 46349 is a highly potent, selective antagonist of serotonin in vitro and is to be considered as a potent, orally active antithrombotic agent.

 

  • References

  • 1 De Clerck F, Van Nueten J. Platelet mediated vascular contractions. Inhibition of the serotoninergic component by ketanserin. Thromb Res 1982; 27: 713-727
    CrossrefPubMedGoogle Scholar
  • 2 De Clerck F, Somers Y, Van Grop L. Platelet-vessel wall interactions in hemostasis: implication of 5-hydroxytryptamine. Agents Actions 1984; 15: 627-635
    CrossrefPubMedGoogle Scholar
  • 3 Ashton JH, Benedict CR, Fitzgerald C, Raheja S, Taylor A, Campbell WB, Buja LM, Willerson JT. Serotonin as a mediator of cyclic flow variations in stenosed canine coronary arteries. Circulation 1986; 73: 572-578
    CrossrefPubMedGoogle Scholar
  • 4 Ashton JH, Golino P, Mcnatt JM, Buja LM, Willerson JT. Serotonin S2 and thromboxane A2-prostaglandin H2 receptor blockade provide protection against epinephrine-induced cyclic flow variations in severely narrowed canine coronary arteries. J Am Coll Cardiol 1989; 13: 755-763
    CrossrefPubMedGoogle Scholar
  • 5 Bush LR, Evans RM, Gaul SL, Reitz PM. Effects of serotonin antagonists, cypropheptadine, ketanserin and mianserin, on cyclic flow reductions in stenosed canine coronary arteries. J Pharmacol Exp Ther 1987; 240: 674-682
    PubMedGoogle Scholar
  • 6 Wilson HC, Coffman W, Killam AL, Cohen ML. LY 53857, a 5-HT2 receptor antagonist, delays occlusion and inhibits platelets aggregation in a rabbit model of carotid artery occlusion. Thromb Haemostas 1991; 66: 355-360
    PubMedGoogle Scholar
  • 7 Maffrand JP, Bernat A, Delebassee D, Defreyn G, Cazenave JP, Gordon JL. ADP plays a key role in thrombogenesis in rats. Thromb Haemostas 1988; 59: 225-230
    PubMedGoogle Scholar
  • 8 Verstraete M. Prevention of atherosclerotic complications with ketanserin. Br J Med 1989; 298: 424-429
    CrossrefPubMedGoogle Scholar
  • 9 Brogden RN, Sorkin EM. Ketanserin. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in hypertension and peripheral vascular disease. Drugs 1990; 40: 903-49
    CrossrefPubMedGoogle Scholar
  • 10 Kennis LEJ, Vanderberk J, Boey JM, Mertens JC, Van Heertum AHM. Janssen M. Awouters F. The chemical development of selective and specific serotonin S2-antagonists. Drug Dev Res 1986; 8: 133-140
    CrossrefPubMedGoogle Scholar
  • 11 Leysen JE, Gommeren W, Van Gompel H, Wyans J, Janssen PAJ, Laduron PM. Receptor-binding properties in vitro and in vivo of ritanserin: A very potent and long acting serotonin-S2 antagonist. Mol Pharmacol 1985; 27: 600-611
    PubMedGoogle Scholar
  • 12 Hara H, Kitajima A, Shimada H, Tamao Y. Antithrombotic effect of MCI-9042, a new antiplatelet agent on experimental thrombosis models. Thromb Haemostas 1991; 66: 484-488
    PubMedGoogle Scholar
  • 13 Rinaldi-Carmona M, Congy C, Santucci V, Simiand J, Gautret B, Neliat G, Labeeuw B, Le Fur G, Soubrie P, Breliere JC. Biochemical and pharmacological properties of SR 46349B a new potent and selective 5-HT2 receptor antagonist. J Pharmacol Exp Ther 1992; 262: 759-768
    PubMedGoogle Scholar
  • 14 Born GV. Aggregation of blood platelets by adenosine diphosphate and its reversal. Nature (London) 1962; 194: 927-929
    PubMedGoogle Scholar
  • 15 Hallam TJ, Scrutton MC. Responses of rabbit platelets to adrenaline induced by other agonists. Thromb Res 1981; 20: 413-424
    PubMedGoogle Scholar
  • 16 Umetsu T, Sanai K. Effect of KC-6141, and anti-aggregating compound, on experimental thrombosis in rats. Thromb Haemostas 1978; 39: 74-83
    PubMedGoogle Scholar
  • 17 Shand RA, Smith JR, Wallis RB. Expression of the platelet procoagulant activity in vivo in thrombus formation in an extracorporeal shunt in the rat. Thromb Res 1984; 36: 223-232
    CrossrefPubMedGoogle Scholar
  • 18 Buchanan MR, Boneu B, Ofgosu FA, Hirsh J. The relative importance of thrombin and factor Xa inhibition to the antithrombotic effect of heparin. Blood 1985; 65: 198-201
    PubMedGoogle Scholar
  • 19 Harker LA, Ritchie JL. The role of platelets in acute vascular events. Circulation 1980; 62: V13-V19
    PubMedGoogle Scholar
  • 20 Vermylen J, Verstraete M, Fuster V. Role of platelet activation and fibrin formation in thrombogenesis. J Am Coll Cardiol 1986; 8: 2B-9B
    CrossrefPubMedGoogle Scholar
  • 21 Bevers EM, Rosing J, Zwaal RFN. Platelets and coagulation. In: Platelets in Biology and Pathology III. Mac Intyre DE, Gordon JL. (eds) Elsevier; Amsterdam: 1987: 127-160
    Google Scholar
  • 22 De Clerck F, De Chaffoy. de Courcelles D. Amplification mechanisms in platelet activation. In: Blood Cells and Arteries in Hypertension and Atherosclerosis. Meyer P, Marche P. (eds) Raven Press; New York: 1989. -105 140
    Google Scholar
  • 23 Vanhoutte PM, Houston DS. Platelets, endothelium and vasospasm. Circulation 1985; 72: 728-734
    CrossrefPubMedGoogle Scholar
  • 24 Willerson JT. Serotonin and thrombotic complications. J Cardiovasc Pharmacol 1990; 17: S13-S20
    PubMedGoogle Scholar
  • 25 De Clerck F, Xhonneux B, Leysen J, Janssen PAJ. Evidence for functional 5-HT2 receptor sites on human blood platelets. Biochem Pharmacol 1984; 8: 2807-2811
    PubMedGoogle Scholar
  • 26 Da Prada M, Picotti GB. Content and subcellular localization of catecholamines and 5-hydroxytryptamine in human and animal blood platelets. Br J Pharmacol 1979; 65: 653-662
    CrossrefPubMedGoogle Scholar
  • 27 McBride PA, Mann JJ, Polley MJ, Willey AJ, Sweeney JA. Assessment of binding indices and physiological responsiveness of the 5-HT2 receptor on human platelets. Life Sci 1987; 40: 1799-1809
    CrossrefPubMedGoogle Scholar
  • 28 Baumgartner HR, Born GVR. The relation between the 5-hydroxy-tryptamine content and aggregation of rabbit platelets. J Physiol 1969; 201: 397-408
    CrossrefPubMedGoogle Scholar
  • 29 Hemker HC, Lindhout MJ, Vermeer C. Blood coagulation factors at phospholipid surfaces. Ann NY Acad Sci 1977; 283: 104-110
    CrossrefPubMedGoogle Scholar
  • 30 Mann KG, Tracy PB, Jenny RJ, Odegaard BH, Nesheim ME. Platelets and coagulation. In Eleventh Congress in Thrombosis and Hemostasis. Verstraete M, Vermylen J, Lijnen R, Amout J. (eds) Leuven University Press; Leuven: 1987. 88 505-23
    Google Scholar
  • 31 Nawroth PP, Stem DM. Endothelial cells as active participants in procoagulant reactions. In Vascular Endothelium in Hemostasis and Thrombosis. Gimbrone GA. (ed) Churchill Livingstone; New York: 1986: 14-39
    Google Scholar
  • 32 Wagner B, Schneider B, Blöchl-Daum B, Speiser W, Eichler HG, Lechner K, Kyrle PA. Effect of ritanserin, a 5-hydroxytryptamine 2-receptor antagonist, on platelet function and thrombin generation at the site of plug formation in vivo. Clin Pharmacol Ther 1990; 48: 419-423
    CrossrefPubMedGoogle Scholar
  • 33 Buczko W, Gambino MC, De Gaetano G. Prolongation of the tail bleeding time by ketanserin: mechanism of action. Eur J Pharmacol 1984; 103: 261-268
    CrossrefPubMedGoogle Scholar
  • 34 De Clerck F, van Nueten JM. Platelet-mediated vascular contractions: inhibition of the serotonergic component by ketanserin. Thromb Res 1982; 27: 713-727
    CrossrefPubMedGoogle Scholar
  • 35 Willerson JT, Golino P, Eidt J, Campbell WB, Buja LM. Specific platelet mediators and unstable coronary artery lesions; experimental evidence and potential clinical implications. Circulation 1989; 80: 198-205
    CrossrefPubMedGoogle Scholar
  • 36 Yao SK, Ober JC, McNatt J, Benedict CR, Rosolowsky M, Anderson V, Cui K, Maffrand JP, Campbell WB, Buja LM, Willerson JT. ADP plays an important role in mediating platelet aggregation and cyclic flow variations in vivo in stenosed and endothelium-injured canine coronary arteries. Circ Res 1992; 70: 39-48
    CrossrefPubMedGoogle Scholar