Effect of structural analogues of PAF-acether on platelet desensitization

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Abstract
The 1-0-alkyl-2-0-acetyl-sn-glyceryl-3-phosphorylcholine (PAF-acether) aggregates rabbit platelets and desensitizes them to a second challenge with the same agonist but not to arachidonic acid. The desensitizing activities of 14 analogs of PAF-acether [1-O-hexadecyl-2-O-propionyl-rac-glyceryl-3-phosphorylcholine; 1-O-hexadecyl-2-O-butyryl-rac-glyceryl-3-phosphorylcholine; 1-O-octadecyl-2-O-methyl-rac-glyceryl-3-kphosphorylcholine; 1-O-octadecyl-2-O-succinyl-rac-glyceryl-3-phosphorylcholine; 1-O-palmitoyl-2-O-acetyl-sn-glyceryl-3-phosphorylcholine; 1-O-stearoyl-2-O-acetyl-sn-glyceryl-3-phosphorylcholine; 1-O-hexadecyl-2-O-acetyl-rac-glyceryl-03--phosphoryl-N,N-dimethylethanolamine; 1-O-octadecyl-2-O-acetyl-sn-glyceryl-3-phosphorylcholine; 3-O-octadecyl-2-O-acetyl-sn-glyceryl-1-phosphorylcholine; 1-O-ocadecyl-2-O-benzyl-rac-glyceryl-3-phosphorylcholine; 1-O-octadecyl-sn-glyceryl-3-phosphorylcholine; 1-O-hexadecyl-2-O-acetyl-sn-glyceryl-3-phosphorylcholine: 1-O-octadecyl-2-O-ethyl-rac-glyceryl-3-phosphorylcholine; and 1-O-hexadecyl-2-o-acetyl-rac-glyceryl-3-phosphorylethanolamine] were explored with particular attention to the dose-response dependency of the desensitization process. PAF-acether was 500-fold more active than its 1-0-acyl analog. The 2-lyso PAF-acether was inactive and the PAF-acether enantiomer 2000 times less effective than the natural isomer, thus confirming the importance of the presence and steric position of the 2-acetate group. The desenstizing activities of the 2-propionyl and the 2-butyryl analogs were close to that of PAF-acether. Substituting an ether to an ester bond at the 2-position indicated that the number of carbon of the 2-substituant seems more determinant than the nature of the linkage for the desensitizing process. The 2-ethoxy and the 2-methoxy analogs were 87 and 5000 times less active than PAF-acether respectively. The presence of methyl groups on the nitrogen base is also critical to desensitize platelets. The desensitizing potency of the tested phospholipids was always identical to their aggregating efficiency. These compounds apparently activate through a common mechanism.

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