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 thei r in vitro biological activities measured. Substituent at position 2 i s 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 mediu m is obtained with 5c, IC50 = 6 x 10(-8) M, which displaces the [H-3]P AF from platelet membrane with an EC(50) = 6 x 10(-8) M, and compound 4 presents an EC(50) of 3 x 10(-8) M. Examination of structure-activit y 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 int o account instead of a pure hydrophobic interaction of the appendix Z into the receptor. The role of the methoxy groups in producing a poten t antagonistic activity is demonstrated by syntheses of several 2-octy lpiperazine analogs. These specific features will be quantitatively an alysed in the following related publication (part 3).