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Biomedical subjects

F Heymans

Publications and source records attributed to F Heymans.

At least 37 records · Page 2Linked to original sources
PubMed1988

Structure-activity relationship in PAF-acether. 4. Synthesis and biological activities of carboxylate isosteres.

The synthesis and biological characterization of some 3-carboxylate isosteres of PAF-acether structurally modified in positions 1 (ether, carbamate), 2 (acetoyl, ethoxy), and 3 (chain length and polar head group) are reported. All derivatives present antagonist activities against PAF-acether-induced effects in vitro (platelet aggregation) and in vivo (bronchoconstriction and thrombocytopenia in guinea pig and, to a lesser extent, hypotension in rat). The functional modifications presented here do not modify dramatically the potency of antagonist activities, and there is no enantioselectivity. All of the isosteres are specific PAF-acether antagonists, except the 1-carbamoyl analogue, which is also potent against acetylcholine-induced hypotension and bronchoconstriction.

Animals↗
PubMed1987

Alkyl analogs of diacylglycerol as activators of protein kinase C.

Diacylglycerols which activate protein kinase C have the 1,2-sn configuration. Short-chain saturated fatty acids or long-chain unsaturated fatty acids are required for supporting the potency of these lipids. Using alkyl analogs such as 1-O-decyl-2-O-decanoylglycerol, 1-O-decanoyl-2-O-decylglycerol, 1,2-O-didecylglycerol, 1-O-hexadecyl-2-O-acetylglycerol and 1-O-decyl-2-O-acetylglycerol, we showed that the ether bond was consistently associated with a loss of activity to varying extents. The results suggest that the ester bond in the 1-position is a major determinant of diacylglycerol-mediated protein kinase activation.

Animals↗
PubMed1987

Effects of a new anorectic drug (PM 170) on development of gold thioglucose-induced obesity in mice.

Gold thioglucose (GTG)-injected mice and lean mice were treated for 16 days with PM 170. The body weight and body fat were significantly increased by GTG injection and these increases in the GTG-obese group were reduced by PM 170. PM 170 also reduced food intake (16%), total body triacylglycerol (51%) and total body cholesterol (36%). Basal lipolysis of white adipose tissue, as measured by glycerol release, was stimulated by 150%. Compared to GTG-PM 170 mice, body weight gain was 2 times higher in GTG-pair-fed mice. Body fat and total body lipid content remained elevated.

Adipose Tissue↗
PubMed1987

Structure-activity relationship in PAF-acether. 3. Hydrophobic contribution to agonistic activity.

The synthesis of some selected PAF-acether homologues with an alkoxy-chain length from C1 to C20 in position 1 is described. All agonist activities are closely correlated among themselves and with the calculated fatty-chain hydrophobicity. After a discussion on recent published results and comparison with our data, we conclude that the ether oxide function is absolutely essential at the glycerol 1-position for potent agonist activity and that potency correlates well with hydrophobicity parameters. We indicate the importance of steric and configurational constraints.

Animals↗
PubMed1986

Effects of PAF-acether and structural analogues on platelet activation and bronchoconstriction in guinea-pigs.

PAF-acether (platelet-activating factor) (1-O-alkyl-2-acetyl-sn-glycerol-3-phosphorylcholine) induces platelet-dependent bronchoconstriction in the guinea-pig which correlates with its in vivo thrombocytopenic effect. We investigated the influence of modifications of the polar head group in position 3 of the glycerol skeleton of PAF-acether on guinea-pig platelet activation and bronchoconstriction. PAF-acether itself induced concentration-dependent platelet activation (EC50 for aggregation = 0.41 nM and EC20 for secretion of ATP = 0.56 nM). The 3-phosphoryl-N-methyl-morpholino ethanol analogue was slightly more active than PAF-acether and the 3-phosphoryl-N-methyl-piperidinium ethanol, 3-phopshoryl-(N-methyl-piperidino-3') methanol and 3-phosphoryl-(N-methyl-hydroxy-4') piperidine analogues were equieffective to PAF-acether in activating platelets. The 3-phosphoryl-piperidino ethanol analogue was 8 times less active than PAF-acether; the 3-phosphoryl-morpholino ethanol analogue and the 1-O-octadecyl-2-O-acetyl-3-O-[trimethyl-ammonio)-propyl) glycerol were inactive up to 1 microM. Our data show that the choline head group is not a compulsory requirement for activity. When injected i.v. to the propranolol-treated guinea-pigs, the platelet-activating analogues also induced bronchoconstriction. Two PAF-acether antagonists, compounds 48740 RP and BN 52021, inhibited PAF-acether-induced platelet activation when added to PRP at the final concentration of 0.1 mM (aggregation inhibited by 91 +/- 4 and by 94 +/- 3% respect.; secretion inhibited by 80 +/- 12 and 79 +/- 10% respectively, mean +/- S.E.M., n = 4). Both antagonists also suppressed platelet activation and in vivo bronchoconstriction, thrombocytopenia, leukopenia and hypotension induced by PAF-acether and the various analogues. Our results indicate that PAF-acether and the analogues studied trigger platelet activation and the consequent bronchoconstriction through mechanisms which share sensitivity to same antagonists.

Adenosine Triphosphate↗
PubMed1982

Biosynthesis of platelet-activating factor. I. Evidence for an acetyl-transferase activity in murine macrophages.

Platelet-activating factor (PAF-acether; 1-0-alkyl-2-acetyl-sn-glyceryl-3-phosphorylcholine) is released from murine peritoneal adherent cells by inflammatory and non-inflammatory stimuli. We have found, in extracts from these cells, an enzyme activity that synthesizes. PAF-acether from synthetic lyso-PAF-acether by transferring the acetyl moiety of acetyl-coenzyme A onto the lyso-PAF-acether molecule. The enzyme is stabilized by 1 mM dithiothreitol, is calcium-dependent, has an apparent Km of 172 microM for acetyl-CoA and is active in a 6-8 pH range. When the acetyl-CoA substrate is replaced by propionyl-CoA, an ether lipid is produced which turns out to be as potent an aggregating agent as PAF-acether. In all cases, the products of the reaction were characterized by their behaviour in platelet-aggregation tests and their high-pressure liquid chromatography (HPLC) elution profiles. The precise definition of this acetyl-transferase is of primary importance for the development of new pharmacological agents capable of moduling a potent platelet aggregating factor.

Acetyltransferases↗
PubMed1982

Radio-labelling of 1-O-alkyl, 2-O-acetyl, sn-glycero-3-phosphorylcholine, 1-O-(9,10-di3H)-octadecyl PAF-acether.

3H-labelling of 1-3H-PAF-aceter was prepared by catalytic reduction of 1-O-(9,10)-octadecenyl-2-O-benzyl-sn-glyceryl-3-phosphorylcholine and then acetylated. 5 mumoles of this dehydro derivative dissolved in methanol was treated during 4 hours with tritium gas (80 Ci) and compressed until 1.1 bar by an automatic tritium transfer unit [1]. The catalyst was removed by filtration over Millex (Millipore) and labile tritium atoms eliminated by rotatory flash evaporation. The chemical purity was checked by 3H scanning and autoradiography. It was finally recovered through preparative thin-layer chromatography and then acetylated. The specific radioactivity was found to be close to 40-50 Ci/mmole.

Isotope Labeling↗
PubMed1981

New total synthesis and high resolution 1H NMR spectrum of platelet-activating factor, its enantiomer and racemic mixtures.

A new method of synthesis of octadecyl platelet-activating factor (PAF; 1-O-octadecyl 2-O-acetyl sn-glycero-3-phosphorylcholine) is described. Its advantage is to proceed by way of the 'lyso-PAF' which may be substituted by various groups, while avoiding the inconveniences of the total synthesis already described. Moreover, the intermediates in synthesis are easier to purify, with better yields. The platelet-aggregating activity of synthetic PAF, is enantiomer (3-O-octadecyl) and racemic mixtures were 2.7 . 10(-10), 1.7 . 10(-7) and 2.2 . 10(-10) M, respectively. These results indicate the stereospecificity of platelet activation induced by PAF.

Animals↗
PubMed1980

Quantitative structure-activity relationships for N-[N',N'-disubstituted-amino)acetyl]arylamines for local anesthetic activity and acute toxicity.

The synthesis and physicochemical properties of a series of N-[N',N'-disubstituted-amino)acetyl]arylamines are described. A QSAR method is applied to local anesthetic activity and acute toxicity by means of a "nonclassic" substituent variation involving a modification on both aryl and amino moieties. The choice of the different parameters (partition coefficient, pKa, connectivity index, molar refraction, and molar volume) is discussed and their different methods of determination are described. Molar refraction is the parameter which explains best the variance of the local anesthetic activity, and the quadratic regression with MR leads to a "posteriori" synthesis of one compound with optimized activity. However, the partition coefficient is the most explicative parameter for intravenous toxicity.

Amines↗