THE BIOLOGICAL-ACTIVITY OF ACETYLATED SPHINGOSYLPHOSPHORYLCHOLINE DERIVATIVES

Taking into account their stereochemical similarity with 1-O-alkyl-2-a cetyl-sn-glycerol-3-phosphorylcholine (PAF), which is known to exhibit a diverse spectrum of biological actions, including platelet aggregat ing and glycogenolytic activity, the acetylated derivatives of sphingo sylphosphorylcholine and sphingomyelin were synthesized and tested for their ability to promote washed rabbit platelet aggregation and glyco genolysis in Tetrahymena pyriformis cells. Sphingomyelin (SPM) and sph ingosylphosphorylcholine (SPC) were subjected to acetylation, followin g chromatographic purification and physicochemical characterization. T he synthesized compounds N-acetyl, O-acetyl SPC (NAc, OAc SPC), N-acet yl SPC (NAc SPC) and O-acetyl SPM (OAc, SPM) were tested far their bio logical activity in the washed rabbit platelets and washed Tetrahymena pyriformis cell systems. These derivatives induced [H-3] serotonin an d ATP release and a monophasic aggregation of washed rabbit platelets in the concentration range 10(-8)-10(-6) M, However, authentic PAF-ind uced washed rabbit platelet aggregation was inhibited at higher concen trations of the acetylated sphingophospholipid compounds (> 10(-6) M) and by the PAF-specific receptor(s) antagonists kadsurenone and triazo lam. Platelet desensitization and crossed desensitization experiments with authentic PAF and the acetylated sphingophospholipids, suggested interaction with the same receptor(s) as PAF and different from the AD P or thrombin receptor. The involvement of calmodulin and protein kina se C in the biological activity of the prepared analogues was also dem onstrated. Besides their action on rabbit platelets, the PAF-like acti vity of the acetylated sphingophospholipids was also demonstrated in a platelet-independent system, by showing that they stimulate glycogeno lysis in washed Tetrahymena pyriformis cells. These observations indic ate that a new class of compounds with PAF-like activity were synthesi zed, but their role in the cellular metabolism remains to be shown. Th e existence of acetylated sphingophospholipids with PAF-like activity has so far been reported only in Urtica dioica.