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J J Godfroid

Publications and source records attributed to J J Godfroid.

At least 37 records · Page 2Linked to original sources
PubMed1996

Structure-activity relationships in platelet-activating factor (PAF). 8. Tetrahydrofuran derivatives as dual PAF antagonists and acetylcholinesterase inhibitors: anti-acetylcholinesterase activity and comparative SAR.

2,5-disubstituted tetrahydrofuran derivatives display a dual functionality: they are PAF antagonists and acetylcholinesterase (AChE) inhibitors. In vitro anti-AChE activity and in vivo trials are presented herein. These compounds are competitive and potent AChE inhibitors. Structure-activity relationships are described and compared with PAF-antagonist results. The presence of an onium group, a suitable distance supplied by a chain of 7 or 10 carbon atoms separating the function from the polar head and an appreciable chain hydrophobicity (4 < sigma f < 7) are the main features required for a dual activity. The derivatives are evaluated in a mouse passive avoidance model. Only compounds with both activities are able to reverse scopolamine-induced amnesia. In addition, they display a very weak toxicity.

Acetylcholinesterase↗
PubMed1996

Effect of S-21663 (PMS 812), an imidazoline derivative, on glucose tolerance and insulin secretion in a rat model of type II diabetes.

We have studied the activity of S-21663 (PMS 812), a new imidazoline derivative, in a rat model of Type II diabetes obtained by i.v. injection of a low dose (35 mg/kg) of streptozotocin, using glucose tolerance tests. Glucose tolerance and insulin secretion were measured as the delta G and the delta l, i.e., the respective increase in glycemia and insulinemia over 30 min after the glucose load. The rate of glucose disappearance was calculated as the K coefficient and the insulin response to glucose as the delta l/delta G. After i.p. injection of S-21663, delta G (millimoles per liter per minute) was decreased (71.7 +/- 10.1 vs. 112.6 +/- 15.1; P < .05), whereas K was increased (3.3 +/- 0.3 vs. 1.5 +/- 0.1; P < .05). Insulin secretion was also largely improved (delta l/delta G: 90.9 +/- 22.2 vs. 18.3 +/- 2.6; P < .05). Oral administration of the product was almost as efficient as i.p. injection. Chronic treatment (15 days) increased the efficiency. Insulin secretion measured in vitro at both 2.8 and 16.6 mM glucose was quadrupled by S-21663 (100 microM). S-21663 binds neither to alpha-2 adrenoceptors nor to known imidazoline binding sites. S-21663 can be considered as a potential hypoglycemic agent in Type II diabetes.

Animals↗
PubMed1993

Design and modeling of new platelet-activating factor antagonists. 1. Synthesis and biological activity of 1,4-bis(3',4',5'-trimethoxybenzoyl)-2-[[(substituted carbonyl and carbamoyl)oxy]methyl]piperazines.

To further investigate our hypothesis on the structure of the platelet-activating factor (PAF) receptor, 35 compounds derived from 1,4-bis(3',4',5'-trimethoxybenzoyl)piperazine were synthesized and their in vitro antagonistic effect was measured. Substitution of the compounds in position 2, by ester or carbamate groups, giving increased steric hindrance and hydrophobicity, increased the platelet aggregation inhibitory activity from 2 microM (without substitution, compound 2) to 0.07 microM (compound 1h) and gave a maximum displacement of [3H]PAF from platelet membrane of 0.05 microM (compound 1k). It appears that the PAF antagonistic effect is only weakly enantiospecific, as observed in many cases including antagonists structurally related or not to PAF. 3D electrostatic potential maps (calculated at -10 kcal/mol) of such compounds revealed a double "Cache-oreilles" (ear-muffs) system. One of these systems has been previously described (distance between atoms generating negative wells, 11-14 A). The second shorter "Cache-oreilles" (6-7 A) system appears to be required for increased PAF antagonistic activity. This short distance between groups generating the negative wells is present in the gingkolides, a series of naturally occurring PAF antagonists. The present study indicates that the structure of the PAF receptor may be more complicated than our initial hypothesis and may be a tetrapolarized structure, with alternants of electropositive and hydrophobic areas. This modified hypothesis is in agreement with recent publications concerning PAF antagonists bearing a cationic moiety.

Animals↗
PubMed1992

Production and characterization of antibodies to platelet-activating factor.

Antibodies directed against platelet-activating factor (PAF) have been raised in rabbits immunized with a novel platelet-activating factor analogue-conjugate. An analogue of PAF with a carbon double bond at the terminal end of the alkyl chain was subjected to ozonolysis and converted to the aldehyde. The aldehyde was coupled to thyroglobulin by reductive alkylation and rabbits were immunized via either intramuscular or intradermal routes in complete Freund's adjuvant. The antibodies are specific for PAF with a preference for the optically active (R)-enantiomer. There appears to be a requirement for antibody binding of an alkyl chain of up to 18 Carbon atoms at C1, and an acetyl group in the C2 position. The ability of a number of structural analogues to inhibit binding of tracer to the antibody is related to the biological activity of the analogue, and therefore may reflect the structural domains that are critical for PAF to interact with its receptor.

Animals↗
PubMed1992

Structure-activity relationships in platelet-activating factor (PAF antagonists). 6. Synthesis and in vitro antagonistic activities of 2-substituted 5-oxotetrahydrofurans.

The synthesis of 2,5-disubstituted tetrahedrofuran compounds as potential in vitro PAF antagonists is described. Results demonstrate that the structural requirements for potent PAF antagonist activity are: a moderate lipophilic group or a trimethoxyphenyl group in position-5, and a long aliphatic chain terminated by a cationic polar head in position-2. The cis-trans configuration does not induce any difference in biological activity. Some conformational features of the putative PAF receptor are proposed in light of the present findings.

Animals↗
PubMed1991

PAF-receptor. III. Conformational and electronic properties of PAF-like agonists and antagonists.

In order to compare electronic and conformational properties of PAF-agonists and PAF-antagonists, 14 analogues structurally related to PAF were studied. A common conformation of the glycerol backbone was present in all agonists and all constrained or flexible antagonists. The distinction between agonists and antagonists appears to be casted on position-2 where the folded conformation of the substituent for agonists should be the most probable. In position-3 the gauche conformation can be adopted by all the analysed compounds. The electrostatic potential well at -30 kcal/mol stretches to the carbonyl group in position-2 in the folded conformation of the agonists. On the contrary, in constrained antagonists, a second negative zone appears around the carbamate group. Given the modelling results, the triethylammonium PAF analogue considered in literature as a weak agonist, was resynthesized and proved to be more potent than previously reported. These experimental results confirm our hypothesis in terms of a common conformation of agonist and antagonist PAF-like molecules.

Electricity↗
PubMed1991

Platelet activating factor antagonists. Structure of N,N'-bis(3,4,5-trimethoxybenzoyl)-2-piperazinylmethyl 2,2-dimethylpropanoate.

Racemic title compound, C30H40N2O10, Mr = 588.65, triclinic, P1-, a = 10.154 (7), b = 11.820 (9), c = 15.038 (8) A, alpha = 96.02 (5), beta = 1.07.54 (4), and gamma = 110.34 (5) degrees, V = 1569 (2) A3, Z = 2, Dx = 1.25 g cm-3, Cu K alpha, lambda = 1.5418 A, mu = 7.4 cm-1, F(000) = 628, T = 293 K, R = 0.0470, wR = 0.0481 for 1961 unique observed reflections. The piperazine ring adopts a chair conformation and the molecule shows limited flexibility of the pseudo-twofold-related trimethoxybenzoyl moieties. The planes through the piperazine and the two trimethoxyphenyl rings are oriented almost perpendicular to each other. Apart from a few possible weak hydrogen bonds, the molecules are held together by weak pi overlap and van der Waals forces.

Molecular Conformation↗
PubMed1991

PAF receptor structure: a hypothesis.

Different hypotheses of the structure of platelet-activating factor (PAF) receptor based on structure-activity relationships of agonists and antagonists are reviewed. For an agonistic effect, strong hydrophobic interactions and an ether function are required in position-1 of the glycerol backbone; chain length limitations and steric hindrance demand a small group in position-2. The unusual structural properties of non-PAF-like antagonists required 3-D electrostatic potential calculations. This method applied to seven potent antagonists suggests a strong "Cache-orielles" (ear-muff) effect, i.e., two strong electronegative wells (isocontour at -10 Kcal/mole) are located at 180 degrees to each other and at a relatively constant distance. Initial consideration of the "Cache-oreilles" effect implied the structure of a bipolarized cylinder of 10-12 A diameter for the receptor. However, very recent results on studies with agonists and antagonists structurally similar to PAF suggest that the receptor may in fact be a multi-polarized cylinder.

Models, Molecular↗
PubMed1991

PAF receptor and "Cache-oreilles" effect. Simple PAF antagonists.

Nine simple and structurally flexible PAF antagonists were synthesized and their inhibitory effects on PAF induced platelet aggregation were measured. Compounds with PAF antagonistic activity exhibited a negative electrostatic potential generated by two trimethoxyphenyl groups (isocontour at -10 Kcal/mole) at various distances between the negative clouds. The optimal distance between the atoms generating the "cache-oreilles" system for exhibiting potent PAF antagonistic activity is estimated to be 11-13 A. In the flexible molecules studied, the dispersion of the electronic distribution is not necessarily favorable for anti-PAF activity. The data support the simple bipolarized model for the PAF receptor that has been proposed by the authors.

Animals↗
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

Endothelium-dependent vasorelaxation induced by Cn-acetal plasmalogens.

In this study the effects of the synthetic acetal plasmalogens (AP) C17-AP, C13-AP, C9-AP on isolated rabbit aorta were investigated with emphasis on their putative relationship with endothelium-dependent relaxing factor (EDRF). The various AP were obtained by total synthesis from the related fatty acid chlorides. In isolated rabbit aorta precontracted with phenylephrine (PE, 10(-7) M), C17-AP (greater than 10(-6) M) and C13-AP (greater than 10(-5) M) exerted an endothelium-dependent relaxation (EDR). In contrast, C9-AP was totally devoid of effect. Given 30 or 45 min before PE, C17-AP (greater than 10(-6) M) and C13-AP (greater than 10(-5) M) abolished the carbachol-induced ERD; moreover, following preincubation with C17-AP, enhanced contraction was obtained with carbachol. Similar effects were obtained with preincubation of aortas with both AA(10(-4) M) and A 23 187 (10(-8) M). Conversely preincubation of aortas with carbachol (3X 10(-6) M) and ATP (3 X 10(-5) M) did not significantly modify the carbachol-induced EDR. Atropine (3 X 10(-7) M) did not affect the relaxation induced by C17-AP and C13-AP. The in vivo effects are correlated with the in vitro actions of acetal plasmalogens: C17-AP and C13-AP but not C9-AP, given iv (5 mg/kg) induced a pronounced but transient hypotension which lasted 2-3 min and which was followed by a persistent hypertensive state. Atropine (0.5 and 1 mg/kg; iv) given 5 min before C17-AP inhibited the secondary hypertensive phase. These results show that C17-AP and C13-AP should be added to the list of compounds capable of releasing EDRF.

Adenosine Triphosphate↗
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↗