KO-286011

The ether phospholipid KO-286011, which is related to platelet-activating factor (PAF), was examined for PAF-antagonistic action on rabbit platelets both in vitro and ex vivo. It inhibited the aggregation of washed platelets induced by PAF (5 nmol/l) concentration dependently (IC₅₀ = 6.5 × 10^-7 mol/l). After injecting 0.5 mg/kg to rabbits, the ex vivo PAF-mediated aggregation in heparinized platelet-rich plasma was influenced selectively. The inhibition was short and maximal after 5 min. In contrast, hematocrit, counts of peripheral platelets and leukocytes, hemoglobin content, partial thromboplastin time, prothrombin time, and fibrinolytic activity in plasma were not affected. However, the therapeutic range of KO-286011 is limited because of membranolytic activity at higher dosages, leading to hemolysis and drop of circulating platelet counts.

A newly synthesised structural analogue of PAF, coded KO-286011 (1-O-hexadecyl-2-O-ethyl-rac-glycero-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. Proaggregatory 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 micrograms/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.