Design and modeling of new platelet-activating factor antagonists. 2. Synthesis and biological activity of 1,4-bis-(3',4',5'-trimethoxybenzoyl)-2-alkyl and 2-alkyloxymethylpiperazines.
In the continuation of our investigations on the structure of platelet-activating factor (PAF)-receptor, 25 additional 2-substituted 1,4-bis-(poly- and mono methoxybenzoyl)-piperazines were synthesized and their in vitro biological activities measured. Substituent at position 2 is representative of the classical balance lipophilicity/hydrophilicity, i.e. alkyl, phenylalkyl, alkoxy and polyalkoxy groups. A potent PAF-induced platelet aggregation inhibitory activity measured in PRP medium is obtained with 5c, IC50 = 6 x 10(-8) M, which displaces the [3H]PAF from platelet membrane with an EC50 = 6 x 10(-8) M, and compound 4 presents an EC50 of 3 x 10(-8) M. Examination of structure-activity relationships shows that molecules bearing a hydrophilic or slightly hydrophobic appendix in position-2 are still potent; their IC50 being included between 10(-6) and 10(-7) M. After quantitative analysis, it seems that in PRP medium, the role of serum albumin must be taken into account instead of a pure hydrophobic interaction of the appendix Z into the receptor. The role of the methoxy groups in producing a potent antagonistic activity is demonstrated by syntheses of several 2-octylpiperazine analogs. These specific features will be quantitatively analysed in the following related publication (part 3).
Tavet
F
F
Laboratoire de Pharmacochimie Moléculaire, Université Paris 7-Denis Diderot, France.
Lamouri
A
A
Heymans
F
F
Dive
G
G
Touboul
E
E
Blavet
N
N
Godfroid
J J
JJ
D000818:Animals; D001792:Blood Platelets / Q000378:metabolism; D015394:Molecular Structure; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D010972:Platelet Activating Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010974:Platelet Aggregation; D010975:Platelet Aggregation Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology; D011817:Rabbits; D013329:Structure-Activity Relationship; D014316:Tritium
D010879:Piperazines; D010972:Platelet Activating Factor; D010975:Platelet Aggregation Inhibitors; D014316:Tritium