Enantioseparation of four cis and trans diastereomers of 2',3'-didehydro-2',3'-dideoxythymidine analogs, by high-performance liquid chromatography and capillary electrophoresis.

Compounds 1-4 are the four stereoisomers of a synthetic new potential antiviral agent (d4T analog) containing two chiral centers and a base (uracil). Both high-performance liquid chromatography (HPLC) and capillary electrophoresis (CE) techniques were used to separate and quantify enantiomers with high resolution. The determination of enantiomeric purity of the compounds was developed using both amylose chiral stationary phase by HPLC and anionic cyclodextrins (highly S-CD) as chiral selectors in CE. The HPLC method was found to be superior in sensitivity to the CE method.

Direct separation of the stereoisomers of methoxytetrahydronaphthalene derivatives, new agonist and antagonist ligands for melatonin receptors, by liquid chromatography on cellulose chiral stationary phases.

Analytical HPLC methods using derivatized cellulose chiral stationary phases were developed for the direct separation of the stereoisomers of disubstituted tetralin derivatives with two chiral centers, new agonist and antagonist ligands for melatonin receptors. The separations were made using normal-phase methodology with a mobile phase consisting of n-hexane-alcohol (methanol, ethanol, 1-propanol or 2-propanol) in various proportions, and a silica-based cellulose tris-3,5-dimethylphenylcarbamate (Chiralcel OD-H), or tris-methylbenzoate (Chiralcel OJ). The effects of concentration of various aliphatic alcohols in the mobile phase were studied. A better separation was achieved on cellulose carbamate phase compared with the cellulose ester phase. The effects of structural features of the solutes on the discrimination between the stereoisomers were examined. Baseline separation (Rs>1.5) was easily obtained in many cases.

Isomers of substituted 3-benzo[b]furyl and 3-thienylaminobutyric acids as potent ligands of the GABA-B receptor: synthesis and preparative liquid chromatographic separation.

Baclofen (4-amino-3-(4-chlorophenyl)butyric acid) is the only selective agonist for GABA-B receptors. Its R-(-)-enantiomer is about 100 times more active than the S-(+)-enantiomer. In the search for new compounds that bind to GABA-B receptors, it is very important to clarify the structural requirements. The authors report the synthesis and separation of isomers of various 3-heteroaromatic (benzo[b]furan and thiophen) aminobutyric acids. The 4-amino-3-(7-methylbenzo[b]furan-2-yl)butanoic acid is a potent and specific ligand for GABA-B receptors, with an IC50 value of 5.4 microM for the displacement of [3H] GABA.

Chiral resolution of the enantiomers of tetrahydronaphthalenic derivatives, new agonist and antagonist ligands for melatonin receptors, using high-performance liquid chromatography on cellulose chiral stationary phases.

Analytical HPLC methods using derivatized cellulose chiral stationary phases were developed for the separation of the enantiomers of methoxy and ethyl tetrahydronaphthalenic derivatives, new agonist and antagonist ligands for melatonin receptors. The resolution were made using normal-phase methodology with a mobile phase consisting of n-hexane-alcohol (methanol, ethanol, 1-propanol or 2-propanol) in various percentage, and a silica-based cellulose tris-3,5-dimethyl-phenylcarbamate (Chiralcel OD-H), or tris-methylbenzoate (Chiralcel OJ). The mobile phase and the chiral stationary phase were varied to achieve the best resolution. The effects of concentration of alcohol, various aliphatic alcohols in the mobile phase were studied. The effects of substitution were analysed. Baseline separation (R(s) > 1.5) was easily obtained in many cases. The resolution results were complementary between the two columns.

GABAB receptor antagonism by resolved (R)-saclofen in the guinea-pig ileum.

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.

Thienyl-GABA derivatives as specific baclofen agonists in the rat and cat spinal cord in vivo.

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.

[Benzoxazolinone phenylethanolamine antagonists of adrenergic receptors. A chemical and pharmacodynamic study]. / Phényléthanolamines benzoxazolinoniques antagonistes des récepteurs adrénergiques. Etude chimique et pharmacodynamique.

Benzoxazolinone can be considered as a bioisosteric analogue of pyrocatechol. This concept has led to the synthesis of benzoxazolinonic phenylethanolamines. The pharmacological study shows that these compounds possess an affinity for adrenergic receptors. Compound (XXXIV), the most interesting, is a competitive alpha and beta adrenergic antagonist which has been studied for antihypertensive activity.

[Alkyl-6-benzoxazolinones. A chemical and pharmacodynamic study]. / Alkyl-6-benzoxazolinones. Etude chimique et pharmacodynamique.

A series of 6-alkylbenzoxazolinones was synthesized by reduction of corresponding acyl derivatives. Two reduction processes were used, Clemmensen reduction and triethylsilane-trifluoroacetic acid reduction, but only the latter represents a general procedure for synthesis of alkyl derivatives. Pharmacological study shows that reduction of the carbonyl group is accompanied by a decrease of analgesic activity with appearance of a psycholeptic profile.