STRUCTURAL FEATURES OF PLATELET ACTIVATING FACTOR (1-ALKYL-2-ACETYL-SN-GLYCERO-3-PHOSPHOCHOLINE) REQUIRED FOR HYPOTENSIVE AND PLATELET SEROTONIN RESPONSES

  • 1 January 1982
    • journal article
    • research article
    • Vol. 38  (1) , 3-20
Abstract
A number of analogs similar in structure to biologically active 1-alkyl-2-acetyl-sn-glycero-3-phosphocholine (platelet activating factor) were tested for their relative effectiveness in lowering the blood pressure of spontaneous hypertensive rats and in releasing [3H]serotonin from rabbit platelets. Except for some minor variations, the 2 test systems gave the same pattern of relative responses for a given analog. Both biological activities (the antihypertensive response and release of platelet serotonin) appear to be stereospecific since the unnatural isomer exhibited no detectable effects. Other structural modifications that greatly reduced (> 500-fold) or eliminated the 2 biological activities were removal of the acetate group, substitution of the acetate group with long-chain acyl, methoxy, benzoxy, N-formyl, N-trifluoroacetyl, N-hexadecanoyl or deoxy groups such as dimethyl, propyl, isopropyl or isobutyl and replacement of the sn-l O-alkyl group with an acyl moiety. Biological activities were reduced to a lesser extent (100- to 500-fold) when the sn-2 C contained butyrate or hexanoate groups or if ethanolamine was substituted for the choline base. Replacing the sn-2 acetate group with an ethoxy group lowered the activity 48- and 120-fold for the blood pressure and serotonin release, respectively. Substitution of propionate for acetate at the sn-2 C gave a compound that was at least, if not more, biologically active than the parent structure; although an N-acetyl analog possessed biologic activities, the responses were only 0.27-1.0% of those obtained with the O-acetyl lipid. Maximum biological activity for both hypotensive effects and platelet serotonin release required a glycerolipid having an alkyl ether at the sn-l, acetate or propionate groups at the sn-2, and phosphocholine at the sn-3 positions.