A series of 30 newly synthesised racemic ether phospholipids was evaluated for PAF-antagonistic action on human blood platelets in vitro. The chemical structure of these compounds was derived from the 1-O-hexadecyl-2-O-ethyl-glycero-3-phosphoric acid 4-(N,N-dimethylamino)pyridinium ethylester which was recently characterised as a PAF-specific antagonist. Anti-PAF effects were demonstrated by means of an aggregation and a binding assay. The inhibition was concentration-dependent and of competitive type. KB-values for inhibiting platelet aggregation in plasma were greater than or equal to 0.3 mumol/l. The most effective antagonists were 3-10 times more effective in comparison with the ginkgolide BN 52021. Structure-activity relationship studies showed the 4-dimethylaminopyridine moiety in the 3 position to be the ultimate structural requirement for expressing PAF-antagonistic activity. Moreover, a short-chain substituent in the 2 position and a distinct distance between the phosphate group and the onium center were found to be essential for high PAF-antagonistic activity.

Blood Platelets↗

PubMedDate not supplied

PAF-agonistic and -antagonistic behaviour of new synthetic ether phospholipids. I. Studies on blood platelets in vitro.

Structural analogues of platelet-activating factor (PAF, 1-O-alkyl-2-O-acetyl-sn-glycero-3-phosphocholine) in which the acetyl group and the polar head have been replaced by ethyl and a pyridine ring, respectively, were tested for biological activities on blood platelets in vitro. In comparison with PAF most of the analogues exerted weak pro-aggregatory effects and both structural modifications were found to contribute to the lowering of platelet-stimulating activity. 1-O-Hexadecyl-2-O-ethyl-rac-glycero-3-phosphoric acid 4-(N,N-dimethylamino)-pyridinium ethylester (DMAP-ethyl-PAF) did not activate platelets but inhibited PAF-induced platelet responses. The inhibition was concentration-dependent and of competitive type. KB values for inhibiting the PAF-induced aggregation of human and rabbit platelets in plasma were 3.2 and 0.55 mumol/l, respectively. There is also evidence that the PAF-antagonistic behaviour of DMAP-ethyl-PAF is attributable to an inhibition of the binding of PAF to its putative receptor.

Humans↗