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Pharmacological properties of YM461, a new orally active platelet-activating factor antagonist

  • PAF Receptor and Antagonists
  • Published:
Lipids

Abstract

The antagonistic effect of YM461 [1-(3-phenylpropyl)-4-[2-(3-pyridyl)thiazolidin-4-ylcarbonyl]piperazine fumarate] against platelet-activating factor (PAF) was examined in severalin vitro andin vivo systems. We found that YM461 inhibited [3H]PAF binding to rabbit platelet membranes with a pKi value of 8.90. YM461 inhibited PAF induced rabbit and human platelet aggregation with pA2 values of 7.52 and 7.29, respectively; the slopes of the Schild plots were 1.07 and 1.01, respectively. However, YM461 at 10−4M did not affect rabbit and human platelet aggregation induced by ADP, collagen, arachidonic acid or epinephrine. YM461 inhibited PAF induced death in mice with an ED50 (50% effective dose) value of 0.35 mg/kgp.o. YM461 at doses above 0.3 mg/kgi.v. inhibited PAF induced hypotension in rats. YM461 showed a dose-dependent inhibition of PAF induced hemoconcentration in rats with ED50 values of 0.15 and 0.21 mg/kgp.o., respectively, at 0.5 and 1 hr after oral administration. The anti-PAF effect of YM461 persisted more than 6 hr after 3 mg/kgp.o. in rats. YM461 inhibited the bronchoconstriction induced by PAF with an ED50 value of 1.2 mg/kgp.o. in anesthetized guinea pigs. Furthermore, the compound at doses above 3 mg/kgp.o. significantly inhibited antigen-induced anaphylactic asthma in conscious guinea pigs pretreated with mepyramine and propranolol. These results indicate that YM461 is a selective, potent and orally active PAF antagonist.

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Abbreviations

BSA:

bovine serum albumin

EC50 :

50% effective concentration

ED50 :

50% effective dose

IC50 :

50% inhibitory concentration

PAF:

platelet-activating factor, 1-O-alkyl-2-acetyl-sn-glycero-3-phosphocholine

PPP:

platelet-poor plasma

PRP:

plateletrich plasma

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Authors and Affiliations

  1. Medicinal Research Laboratories, Yamanouchi Pharmaceutical Co., Ltd., 21 Miyukigaoka, 305, Tsukuba, Ibaraki, Japan

    Toshimitsu Yamada, Munetoshi Saito, Toshiyasu Mase, Hiromu Hara, Hitoshi Nagaoka, Kiyoshi Murase & Kenichi Tomioka

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  1. Toshimitsu Yamada
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  2. Munetoshi Saito
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  3. Toshiyasu Mase
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  4. Hiromu Hara
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  5. Hitoshi Nagaoka
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  6. Kiyoshi Murase
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  7. Kenichi Tomioka
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Yamada, T., Saito, M., Mase, T. et al. Pharmacological properties of YM461, a new orally active platelet-activating factor antagonist. Lipids 26, 1179–1183 (1991). https://doi.org/10.1007/BF02536527

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  • DOI: https://doi.org/10.1007/BF02536527

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