Pascal Berthelot

Synthesis, pharmacology and X-ray studies of baclofen analogues

Baclofen (β-p-chlorophenyl-GABA) is the reference selective agonist for the bicuculline-insensitive GABAB receptor. The search for new compounds having a high affinity for the GABAB receptor is very important to clarify structural requirements. In that sense, we report the synthesis, binding studies and X-ray determinations of various 3-heteroaromatic γ-aminobutyric acids. Biochemical investigations concerning their abilities to displace [3H] muscimol (GABAA) and [3H] baclofen (GABAB) in binding studies showed that the 4-amino-3-(5-methoxybenzo[b]furan-2-yl)butanoic acid 6a (IC50 = 22.16 μM/R (−) [3H] baclofen; IC50 = 5.6 μM/RS [3H] baclofen) has a specific affinity for the GABAB receptor. The crystal structure of compounds 6a and 6b associated with computer graphics molecular superimpositions allows some structural requirements for GABAB receptor ligands to be proposed.

Design and synthesis of benzofuranic derivatives as new ligands at the melatonin-binding site MT3

Benzofuranic analogues of MCA-NAT (5-methoxycarbonylamino-N-acetyltryptamine) have been synthesized and evaluated as melatonin receptor ligands. Introduction of a methoxycarbonylamino substituent in the C-5 position of the benzofurane nucleus obtains MT(3) selective ligands. This selectivity can be modulated with suitable variations of the C-5 position and the acyl group on the C-3 side chain.

Direct separation of 4-amino-3-(4-chlorophenyl)butyric acid and analogues, GABAB ligands, using a chiral crown ether stationary phase

Abstract The direct resolution of baclofen (β- p -chlorophenyl-γ-aminobutyric acid) and a series of four analogues was achieved by HPLC on an enantioselective, crown ether column, CR(+). Chromatography was carried out with perchloric acid as mobile phase and methanol as organic modifier. The effects of temperature, pH, eluent composition and substituents are discussed. The absolute configuration is attributed. The best results were obtained with baclofen (α = 1.48; R s = 8.07).

Preparative resolution of saclofen and hydroxysaclofen with analytical-scale high-performance liquid chromatography

Abstract The preparative enantiomeric resolution of two analogues of baclofen: saclofen and hydroxysaclofen, potent γ-aminobutyric acid B (GABA B ) antagonists, was obtained by HPLC with an analytical crown ether column (CR+) using isocratic conditions and multiple repetitive injections. The preparative separation was optimized by adjusting the sample size, by detecting the sample where its UV absorbance was low and from a scale-up of the analytical method. The analytical separation was modified to provide a convenient method for the isolation of the two enantiomers. The best analytical results obtained were α = 3.68, R s = 20.96 with H 2 Oue5f8CH 3 OH (90:10) at 0.5 ml/min and 20°C for hydroxysaclofen. Suitable fractionation allowed the isolation of pure (>99%) enantiomers for pharmacological testing.

Quantitative structure-activity relationships studies of antioxidant hexahydropyridoindoles and flavonoid derivatives.

In order to predict the antioxidant activity of 22 pinoline derivatives (1,2,3,4-tetrahydro-β-carbolines), two dimensional quantitative-structure activity relationships (2D-QSAR) analysis of 19 hexahydropiridoindoles and 12 flavonoids was realized. Five statistically significant models were obtained from randomly constituted training sets (21 compounds) and subsquently validated with the corresponding test sets (10 compounds). Antioxidant activity (pIC50) was correlated with 5 molecular descriptors calculated with the software DRAGON. The best predictive model (n = 21, q2 = 0.794, N = 2, r2 = 0.888, s = 0.157) could offer structural insights into the features conferring a strong antioxidant activity to compounds built from a pinoline scaffold prior to their synthesis.

Actions of thienyl analogs of baclofen in the guinea-pig isolated ileum

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.

Direct chromatographic separation of the enantiomers of phaclofen, saclofen and hydroxysaclofen : influence of the anionic moiety

Abstract The direct resolution of three analogues of baclofen (phaclofen, saclofen and hydroxysaclofen), potent -γ-aminobutyric acid B antagonists, is achieved by HPLC on an enantioselective crown ether column. The effects of the anionic group are discussed. Perchloric acid and methanol as organic modifier is used as mobile phase. The absolute configuration is proposed by comparison with enantiomers of baclofen (β- p -chlorophenyl-γ-aminobutyric acid). The above-mentioned compounds are easily and completely resolved.

Preparative liquid chromatographic separation of isomers of 4-amino-3-(4-chlorophenyl)butyric acid

Abstract A liquid chromatography method was developed for the chiral resolution of [4-amino-3-(4-chlorophenyl)butyric acid isomers. The compound was derivatized in two steps: protection of the amino group with di- tert .-butyl carbonate and reaction with ( S )-α-methyl benzyl amine to obtain the diastereomeric mixture RS and SS . Chromatography was carried out on silica gel (5–20 μm) employing n -hexane—ethyl acetate as eluent. 1 H NMR spectroscopy and analytical high-performance liquid chromatography indicated that the separated fractions were pure.

GABA-B agonists: enantiomeric resolution of 4-amino-3-(5-chlorothien-2-yl)butyric acid and analogues on chiral crown ether stationary phase

Abstract The enantiomeric resolution of 4-amino-3-(5-chlorothien-2-yl)butyric acid, an analogue of baclofen [4-amino-3-(4-chlorophenyl)butyric acid], was examined by HPLC using a chiral stationary phase consisting of a crown ether and perchloric acid-methanol as the mobile phase. Optimization of the separation was achieved by variation of temperature, pH and eluent composition. The absolute configuration may be assigned by comparison with authentic enantiomers of baclofen of known absolute configuration. The best results obtained were α = 1.15 and Rs = 2.72 at 20°C with HClO4 (pH 1.3)ue5f8CH3OH (90:10). The study was extended to analogues, viz., 3-(substituted thienyl) and 3-(substituted furanyl)-4-amino acids.

New analogues of the anticancer E7070: synthesis and pharmacology.

Cell cycle control in the G1 phase has attracted considerable attention in recent cancer research, because many of the important proteins involved in G1 progression or G1/S transition have been found to play a crucial role in proliferation, differentiation, transformation, and programmed cell death (apoptosis). E7070 is a novel antitumor sulfonamide, with a unique mode of action that affects G1 progression of the cell cycle. A series of compounds containing an N-[1-(3,4,5-trimethoxybenzyl)-1H-indol-5-yl]benzene sulfonamide, analogues of E7070, was synthesized and evaluated as potential antitumor agents. Cell cycle analysis with PC3 human prostate cancer cells revealed a cellular accumulation in the G1 phase.