PAF-agonistic and -antagonistic behaviour of new synthetic ether phospholipids. II. Relationships between chemical structure and inhibition of PAF-induced human platelet activation.
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.
Ostermann
G
G
Institute of Pathological Biochemistry, Medical Academy of Erfurt, G.D.R.
Hofmann
B
B
Kertscher
H P
HP
Till
U
U
D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism*; D004224:Diterpenes; D005069:Evaluation Studies as Topic; D046934:Ginkgolides; D006801:Humans; D007783:Lactones / Q000494:pharmacology; D010742:Phospholipid Ethers / Q000138:chemical synthesis / Q000378:metabolism / Q000494:pharmacology*; D010972:Platelet Activating Factor / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000494:pharmacology; D015539:Platelet Activation / Q000187:drug effects*; D010974:Platelet Aggregation / Q000187:drug effects; D011726:Pyridinium Compounds / Q000494:pharmacology*; D013329:Structure-Activity Relationship
D004224:Diterpenes; D046934:Ginkgolides; D007783:Lactones; D010742:Phospholipid Ethers; D010972:Platelet Activating Factor; D011726:Pyridinium Compounds; C072626:1-O-hexadecyl-2-O-ethyl-rac-glycero-3-phosphoric acid 4-(N,N-dimethylamino)-pyridinium ethylester; C045856:ginkgolide B