Summary
A newly synthesised structural analogue of PAF, coded KO-286011 (1-O-hexadecyl-2-O-ethyl-racglycero-3-phosphoric acid 4-(N,N-dimethylamino)pyridinium butylester), was proved for its ability to inhibit PAF-mediated platelet responses in vitro and in vivo. The compound inhibited effectively the PAF-induced aggregation and secretion of human and rabbit platelets. In contrast, there was little influence on ADP-, collagen-, and arachidonic acid-triggered platelet responses. Schild-analysis of aggregation data ascertained in human platelet-rich plasma was consistent with a simple competitive antagonism and yielded a pA2, of 6.44. Pro-aggregatory activity of KO-286011 was excluded turbidimetrically as well as by means of a single cell counting technique. [3H]PAF binding studies provided evidence that KO-286011 exerts its inhibitory action at the PAF-receptor level. A significant inhibition of the ex vivo PAF-induced platelet aggregation was found after i.v. administration of 0.5 mg/kg KO-286011 to rabbits. The effect was most pronounced 5 min after dosing the inhibitor and detectable over a period of 30 min. Intravenous administration of 10 and 25 µg/kg KO-286011 to guinea pigs prevented dose-dependently the PAF-induced formation of thromboxane A2. The PAF-inhibitory action of KO-286011 was more potent than that of the ginkgolide BN 52021.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Arnout J, Van Hecken A, De Lepeleire I, Miyamoto Y, Holmes I, De Schepper P, Vermylen J (1988) Effectiveness and tolerability of CV-3988, a selective PAF antagonist, after intravenous administration to man. Br J Clin Pharmacol 25:445–451
Berti F, Omini C, Rossoni G, Braquet P (1986) Protection by two ginkgolides, BN-52020 and BN-52021, against guinea-pig lung anaphylaxis. Pharmacol Res Commun 18:775–793
Blank ML, Lee T-C, Fitzgerald V, Snyder F (1981) A specific acetylhydrolase for 1-alkyl-2-acetyl-sn-glycero-3-phosphocholine, a hypotensive and platelet-activating lipid. J Biol Chem 256:175–178
Born GVR (1961) Aggregation of blood platelets by adenosine diphosphate and its reversal. Nature 194:927–929
Born GVR, Hume M (1967) Effects of numbers and size of platelet aggregates on optical density of plasma. Nature 215:1027–1029
Braquet P (1987) The ginkgolides: Potent platelet-activating factor antagonists isolated from Ginkgo biloba L.: chemistry, pharmacology and clinical applications. Drugs Future 12:643–699
Braquet P, Vargaftig BB (1986) Pharmacology of platelet activating factor. Transplant Proc 18:10–19
Braquet P, Godfroid J-J (1987) Conformational properties of the PAF-acether receptor on platelets based on structure-activity studies. In: Snyder F (ed) Platelet-activating Factor and Related Lipid Mediators. Plenum, New York, pp 191–235
Braquet P, Spinnewyn B, Braquet M, Bourgain RH, Taylor JE, Etienne A, Drieu K (1985) BN 52021 and related compounds: a new series of highly specific PAF-acether receptor antagonists isolated from Ginkgo biloba. Blood Vessels 16:559–572
Cooper K, Parry MJ (1989) PAF Antagonists. In: Allen RC (ed) Annual Reports in Medicinal Chemistry, vol 24. Academic, New York, pp 81–90
Cox C (1986) Effects of CV-3988, an antagonist of platelet-activating factor (PAF), on washed rabbit platelets. Thromb Res 41:211–222
Dive G, Godfroid J-J, Lamotte-Braseur J, Batt J-P, Heymans F, Dupont L, Braquet P (1989) PAF-receptor. 1. ‘Cache-coreilles’ effect of selected high-potency platelet-activating factor (PAF) antagonists. J Lipid Mediators 1:201–215
Demopoulos CA, Pinckard RN, Hanahan DJ (1979) Plateletactivating factor. Evidence for 1-O-alkyl-2-acetyl-sn-glycerol-3-phosphocholine as the active component (a new class of lipid chemical mediators). J Biol Chem 254:9355–9358
Fiedel BA (1978) Effects of lysolecithin on aggregation of human platelets induced by arachidonic acid and A 23187, role of prostaglandin intermediary metabolism. Life Sci 22:531–534
Hadvary P, Baumgartner HR (1983) Activation of human and rabbit blood platelets by synthetic structural analogs of platelet activating factor. Thromb Res 30:143–156
Hanahan DJ (1986) Platelet activating factor: A biologically active phosphoglyceride. Ann Rev Biochem 55:483–509
Handley DA (1988) Development and therapeutic indications for PAF receptor antagonists. Drugs Future 13:137–152
Handley DA, Tomesch JC, Saunders RN (1986) Inhibition of PAF-induced systemic responses in the rat, guinea pig, dog and primate by the receptor antagonist SRI 63–441. Thrombos Haemostas 56:40–44
Handley DA, Van Valen RG, Winslow CM, Tomesch JC, Saunders RN (1987) In vitro and in vivo pharmacological profiles of the PAF receptor antagonist SRI 63–675. Thrombos Haemostas 57:187–190
Handley DA, Houlihan WJ, Tomesch JC, Farley C, Deacon RW, Koletar JM, Prashad M, Hughes JW, Jaeggi C (1989) Chemistry and pharmacology of PAF antagonists. Evaluation of changes at potential metabolism sites on activity and duration of activity. In: Samuelson B, Wong PY-K, Sun FF (eds) Advances in Prostaglandin, Thromboxane, and Leukotriene Research, Vol. 19, Raven, New York, pp 367–370
Hwang S-B, Lam M-H (1986) Species difference in the specific receptors of platelet activating factor. Biochem Pharmacol 35:4511–4518
Hwang S-B, Lam M-H, Hsu AH-M (1989) Characterization of platelet-activating factor (PAF) receptor by specific binding of [3H]L-659,989, a PAF receptor antagonist, to rabbit platelet membranes: possible multiple conformational states of a single type of PAF receptors. Mol Pharmacol 35:48–58
Inarrea P, Gomez-Cambronero J, Nieto M, Sanchez-Crespo M (1984) Characteristics of the binding of platelet-activating factor to platelets of different animal species. Eur J Pharmacol 105:309–315
Janero DR, Burghardt B, Burghard Ch (1988) Specific binding of 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine (platelet-activating factor) to the intact canine platelet. Thromb Res 50:789–802
Joist JH, Dolezel G, Cucuianu MP, Nishizawa EE, Mustard JF (1977) Inhibition and potentiation of platelet function by lysolecithin. Blood 49:102–112
Kanaho Y, Kometani M, Sato T, Fujii T (1983) Mechanism of inhibitory effects of some amphiphilic drugs on platelet aggregation induced by collagen, thrombin or arachidonic acid. Thromb Res 31:817–831
Kertscher H-P, Ostermann G, Till U (1986) DDR-Patent 296,659
Kloprogge A, Akkerman JWN (1984) Binding kinetics of PAF-acether 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine to intact human platelets. Biochem J 223:901–909
Lefort J, Wal F, Chignard M, Medeiros MC, Vargaftig BB (1982) Pharmacological properties of PAF-acether in the guinea-pig: Platelet dependent and independent reactions. Agents Actions 12:723–725
McManus LM (1986) Pathobiology of platelet-activating factors. Pathol Immunopathol Res 5:104–117
Muramatsu T, Totani N, Mangold HK (1981) A facile method for the preparation of 1-O-alkyl-2-O-acetoyl-sn-glycero-3-phos-phocholine (platelet activating factor). Chem Phys Lipids 29:121–127
O'Flaherty JT, Salzer WL, Cousart S, McCall CE, Piantadosi C, Surles JR, Hammett MJ, Wykle RL (1983) Platelet-activating factor and analogues: comparative studies with human neutrophils and rabbit platelets. Res Commun Chem Pathol Pharmacol 39:291–308
Ostermann G, Till U, Thielmann K (1983) Studies on the stimulation of human blood platelets by semisynthetic platelet-activating factor. Thromb Res 30:127–136
Ostermann G, Kostner GM, Gries A, Malle E, Till U (1988) The contribution of individual lipoproteins to the degradation of platelet-activating factor in human serum. Haemostasis 19:160–168
Ostermann G, Kertscher H-P, Hofmann B (1990a) Der Plättchenaktivierende Faktor — ein biologisch hochwirksames Phospholipid. Pharmazie 45:465–487
Ostermann G, Hofmann B, Kertscher H-P, Till U (1990b) PAF-agonistic and -antagonistic behaviour of new synthetic ether phospholipids. I. Studies on blood platelets in vitro. J Lipid Mediators 2:21–31
Ostermann G, Hofmann B, Kertscher H-P, Till U (1990c) PAF-agonistic and -antagonistic behaviour of new synthetic ether phospholipids. II. Relationship between chemical structure and inhibition of PAF-induced human platelet activation. J Lipid Mediators 2 (in press)
Saunders RN, Handley DA (1987) Platelet-activating factor antagonists. Annu Rev Pharmacol Toxicol 27:237–255
Schattner M, Parini A, Fouque F, Vargaftig BB (1989) Selective inhibition of adrenaline-induced human platelet aggregation by the structurally related PAF antagonist Ro 19–3704. Br J Pharmacol 96:759–766
Slattery CW, Beaumont DO (1989) Sheep platelets as a model for human platelets: Evidence for specific PAF (platelet activating factor) receptors. Thromb Res 55:569–576
Tai H-H, Yuan B (1978) Development of radioimmunoassay for thromboxane B2. Analyt Biochem 87:343–349
Terashita Z-I, Tsushima S, Yoshioka Y, Nomura H, Inada Y, Nishikawa K (1983) CV-3988, a specific antagonist of platelet-activating factor (PAF). Life Sci 32:1975–1982
Tokumura A, Homma H, Hanahan DJ (1985) Structural analogs of alkylacetylglycerophosphocholine: inhibitory behaviour on platelet activation. J Biol Chem 260:12710–12714
Tokumura A, Yoshioka J-I, Maruyama T, Fukuzawa K, Tsukatani H (1987) Platelet aggregation induced by ether-linked phospholipids. 1. Inhibitory action of bovine serum albumin and structural analogues of platelet activating factor. Thromb Res 46:51–63
Author information
Authors and Affiliations
Additional information
Send offprint requests to G. Ostermann at the above address
Rights and permissions
About this article
Cite this article
Ostermann, G., Hofmann, B., Kertscher, HP. et al. Platelet-activating factor (PAF) inhibitory profile of KO-286011 on blood platelets in vitro and in vivo. Naunyn-Schmiedeberg's Arch Pharmacol 342, 713–718 (1990). https://doi.org/10.1007/BF00175717
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00175717