Biomedical subjects
Publications and source records attributed to M Debaert.
Some new N-substituted pyrrolidin-2-ones, cyclic analogs of baclofen and of 3-(5-methylbenzo[b]furan-2-yl)-gamma-aminobutyric acid, have been prepared starting from corresponding pyrrolidinones and characterized.
Various features of the evolution of a few antimalarial drugs including amodiaquine, dihydrofolate-reductase inhibitors, and artemisinin are described. The mechanism of action of artemisinin is detailed to explain the information of the main metabolites and drug design of certain compounds. Structure-activity and structure-neurotoxicity relations are reported. A few examples of cyclic peroxycetal synthesis are given. Finally, trends in new and novel compounds are presented.
The GABAB receptor antagonist saclofen (3-amino-2-(4-chlorophenyl)propylsulphonic acid) has been resolved by chiral high-performance liquid chromatography. The enantiomer (R)-saclofen, but not (S)-saclofen, reversibly antagonised the (R,S)-baclofen-induced depression of cholinergic twitch contractions in the guinea-pig ileum with an apparent pA2 of 5.3. Also, 2-hydroxy-saclofen was resolved by the same method, its (S)-enantiomer yielding an apparent pA2 of 5.0. This method provides a convenient resolution of these antagonists.
Substituting a furan, a thiophene, a benzo[b]furan, a benzo[b]thiophene, or a quinoline ring for the p-chlorophenyl moiety of baclofen has led to GABAB ligands with different affinities depending on the nature of the heteroaromatic ring, and on the nature and position of its substituent. As steric effects cannot account for all the affinity variations, we have studied the lipophilic and electronic properties of baclofen and selected 3-heteroaromatic analogues, gaining insight into the structural features necessary for GABAB affinity. Centrifugal partition chromatography (CPC) has been used to measure octan-1-ol water distribution coefficients, while ab initio molecular orbital (MO) calculations were performed to study electronic properties.
The depression of the amplitude of extracellularly recorded monosynaptic excitatory field potentials in the lumbar spinal cord of pentobarbitone anaesthetised rats and cats by three thienyl derivatives of GABA: 4-amino-3-(2-thienyl)-butanoic acid; 4-amino-3-(2-thienyl-5-methyl)-butanoic acid and 4-amino-3-(2-thienyl-5-chloro)-butanoic acid was reversibly blocked by the (-)-baclofen antagonist 3-aminopropyl-diethoxymethyl-phosphinic acid (CGP 35348). These compounds, of which the most potent, the 5-chloro derivative, was weaker than (-)-baclofen, thus activate baclofen receptors in the cat and rat spinal cord.
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In the guinea-pig isolated ileum, beta-(2-thienyl)-gamma-aminobutyric acid (BTG; 100-500 microM) reversibly and competitively (pA2 = 4.3 +/- 0.1) antagonised the baclofen-induced (5-100 microM) depression of cholinergic twitch contractions, but not that to adenosine or morphine. By contrast, in rat neocortical slice preparations, BTG (100-500 microM) acted as an agonist, abolishing the frequency and amplitude of spontaneous discharges, sensitive to 2-hydroxysaclofen (100-500 microM). BTG exhibits differential actions at GABAB receptors in brain and periphery.
In guinea-pig isolated ileal preparations, the 5-methylthien-2-yl (5d), 5-bromothien-2-yl (5f) and 5-chlorothien-2-yl (5h) analogs of baclofen depressed twitch responses to field stimulation in a dose-dependent manner. These actions were reversibly and competitively antagonised by 2-hydroxysaclofen but not by naloxone, phentolamine, propranolol or theophylline. The relative potencies (EC50 values) were baclofen (10 microM) greater than 5h (40 microM) greater than 5d (80 microM) greater than 5f (120 microM). These analogs represent a novel class of specific GABAB receptor agonists which, like baclofen, should readily enter the brain.
Baclofen (beta-(p-chlorophenyl)-GABA) is a selective agonist for the bicuculline-insensitive GABAB receptor. The search for new compounds that bind to the GABAB receptor is very important to clarify structural requirements. We report herein the synthesis and the binding studies of variously substituted 3-thienyl- and 3-furylaminobutyric acids. 4-Amino-3-(5-methyl-2-thienyl)butyric acid (5d) and 4-amino-3-(5-chloro-2-thienyl)butyric acid (5h) are potent and specific ligands for GABAB receptor. The IC50 values for the displacement of (R)-(-)-[3H]baclofen are 1.34 and 0.61 microM for 5d and 5h, respectively, as compared to 0.33 microM for baclofen.
Several oximes, hydrazones and dichloroacétamides were synthesized. The antiparasitic properties of these compounds were evaluated in vitro against two Protozoaires Entamoeba histolytica and Trichomonas vaginalis.
In this study, eight new 1-(2-benzoxazolinone-6-yl)-2-(4-arylpiperazine-1-yl)ethanol and -propanol derivatives have been prepared. Their structures have been elucidated by IR- and 1H-NMR-spectra and by elementary analysis. The analgesic activities of these compounds, using modified Koster's test have been investigated. 1-(5-Chloro-3-methyl-2-benzoxazolone-6-yl)-2-[4-(2-methoxyphenyl)p iperazine-1- yl]ethanol has been found more active than O-acetyl-salicylic acid, respectively.
The synthesis of vinylogous of 1,2-dithiole-3-thione is described. The activity in experimental schistosomiasis (schistosomicidal activity) was tested with mice infected with Schistosoma mansoni. The reference compound was 4-methyl-5-(pyrazinyl)-1,2-dithiole-3-thione (oltipraz).
Dosage of lactulose and determination of related sugars (lactose, fructose, galactose, épilactose) were undertaken by high performance liquid chromatography (HPLC). The present note described two modes of detection used simultaneously and compared: refractive index detector (RI) and multiwavelength ultraviolet detector (UV). HPLC is performed with an aminopropylsylil phase as stationary phase and an isocratic mobile phase containing acetonitrile and aqueous sodium phosphate. The results are outlined and discussed.
When administered microelectrophoretically, 4-amino-3-(5-methoxybenzo[b]furan-2-yl)butanoic acid (MBFG) reversibly reduced the presynaptic depression by (-)-baclofen of the monosynaptic excitation of spinal interneurones by impulses in muscle low-threshold afferent fibres of the cat as well as the postsynaptic depression by (-)-baclofen of the firing of these neurones. MBFG, as an antagonist of (-)-baclofen, may be useful in investigating the structure-activity relationships of central and peripheral baclofen receptors.
Two novel beta-(benzo[b]furan) analogues of baclofen (4-amino-3-benzo[b]furan-2-ylbutanoic acid, 9G, and 4-amino-3-(5-methoxybenzo[b]furan-2-yl)butanoic acid, 9H) antagonised the baclofen-induced depression of twitch contractions in the guinea-pig isolated ileum (estimated apparent pA2 3.9 and 4.1 respectively); both 9G and 9H also antagonised in a dose-dependent manner the baclofen-induced reduction of repetitive paroxysmal discharges in rat neo-cortical slice preparations maintained in Mg2+-free Krebs solution. These benzofurans evidently represents a new class of GABAB-receptor antagonist.
The synthesis of new arylpropenones derived from 1-methyl-5-nitro imidazole is described. The investigation of some antiprotozoal properties has shown that compounds with the groups 4-hydroxyphenyl, 4-chlorophenyl or thiophenyl have trichomonacidal activity similar to that of metronidazole.
A description is given of potential cyclic imidazoles such as 3,3-dichloro-2-methylenimino-acrylonitrile derived from nitro or non-nitro heterocycles, as well as the hydrazone, semicarbazone and arylpropenone derivatives of the 4-chloro-2-(5-nitro-2-thienyl) (V), 5-imidazole carboxaldehyde (IV) and the 5-bromothienyl analogue. The antiparasitic activity was tested in vitro against Trichomonas vaginalis and Entameba histolytica. Some of the nitro containing compounds showed trichomonacidal activity whereas one of the non-nitro compounds with potential imidazole structure showed clear amebacidal activity. This compound, 3,3-dichloro-2-methyleneimino acrylonitrile has anti-ameba activity comparable with that of metronidazole.
Baclofen (beta-p-chlorophenyl-GABA) is the only selective agonist for the bicuculline-insensitive GABAB receptor. We report the synthesis of new GABA analogues and baclofen analogues. In vitro, two compounds, 4-amino-3-benzo[b]furan-2-ylbutanoic acid (9g) and 4-amino-3-(5-methoxybenzo[b]furan-2-yl)butanoic acid (9h), showed an affinity for the GABAB receptor. The results obtained with racemic compounds of benzofuran structure, new for this series, and the surprising inactivity of compound 3a (4-amino-3-(4-hydroxyphenyl)butanoic acid) permit the proposal of an hypothesis for the structure-activity relationships with regard to GABAB receptor.