Chromatographic separation of 2,3-benzodiazepines

Rizzo, Milena

doi:10.1016/s0378-4347(00)00269-3

Cited by 10 publications

(6 citation statements)

References 36 publications

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“…The empirical formula is C 19 H 20 N 4 O 3 (molecular weight: 352.4) and the chemical name is (-)1-(4-aminophenyl)-4-methyl-7,8methylenedioxy-4,5-dihydro-3-methylcarbamoyl-2,3-benzodiazepine. GYKI 53784 is soluble in water (2 mg/mL), methanol (14 mg/mL), ethanol (17.6 mg/mL), and DMSO (17.6 mg/mL), and is slightly soluble in n-hexane (2,24,49,70,78,79). The bioavailability of GYKI 53784 has been studied following intravenous administration (79).…”

Section: Chemistrymentioning

confidence: 99%

Negative Allosteric Modulation of AMPA‐preferring Receptors by the Selective Isomer GYKI 53784 (LY303070), a Specific Non‐competitive AMPA Antagonist

2002

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GYKI 53784 or LY303070 [(-)1-(4-aminophenyl)-4-methyl-7,8-methylenedioxy-4,5-dihydro-3-methylcarbamoyl-2,3-benzodiazepine] belongs to a new family of 2,3-benzodiazepine compounds (also called homophtalazines) selective and non-competitive antagonists at á-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA) receptors. These compounds include the original GYKI-52466, its more potent derivative GYKI 53655 and the active isomer of the latter, GYKI 53784. This review summarizes current knowledge of this novel AMPA antagonist: GYKI 53784.GYKI 53784 is the most potent of the compounds in the 2,3-benzodiazepine class, blocking AMPA receptor-mediated responses. In contrast to the compounds of the quinoxalinedione family, that block AMPA as well as kainate receptors, GYKI 53784 does not block the activation of kainate receptors. Furthermore, GYKI 53784 does not act at the same receptor site as positive AMPA modulators (i.e., cyclothiazide, BDP-12, 1-BCP or aniracetam). GYKI 53784 is a powerful neuroprotective agent in both in vitro and in vivo models of AMPA receptor-mediated excitotoxicity.In contrast to NMDA receptor antagonists, whose favorable clinical actions are compromised by important side effects such as the impairment of memory functions, the selective AMPA antagonist, GYKI 53784, may be of potential clinical value, both in acute (stroke and trauma) and chronic (Alzheimer's disease, epilepsy) neurological disorders.

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Section: Chemistrymentioning

confidence: 99%

Negative Allosteric Modulation of AMPA‐preferring Receptors by the Selective Isomer GYKI 53784 (LY303070), a Specific Non‐competitive AMPA Antagonist

2002

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“…The determination of DZP and its metabolites in plasma, brain and cerebrospinal fluid (CSF) would have a significant impact on the study of treatments for various neurological disorders. Several analytical techniques have been published for the determination of DZP and its metabolites, namely high‐performance liquid chromatography (HPLC‐UV),3–11 gas chromatography (GC),12 gas chromatography/mass spectrometry (GC/MS),13–15 and liquid chromatography/mass spectrometry (LC/MS, LC/MS‐MS) 16,17. Most of the biological matrices assayed using these published methods are plasma, serum, blood, and urine from various animal species.…”

mentioning

confidence: 99%

Simple and sensitive liquid chromatography/tandem mass spectrometry method for the determination of diazepam and its major metabolites in rat cerebrospinal fluid

Wang

Shen

Fenyk-Melody

et al. 2003

Rapid Comm Mass Spectrometry

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Diazepam (DZP) is one of the most commonly prescribed drugs for treating status epilepticus (SE). A simple, sensitive and selective LC/MS/MS method with a wide linear calibration range was developed to quantify DZP and its major metabolites, N-desmethyldiazepam (DMDZP), temazepam (TZP), and oxazepam (OZP), in rat cerebrospinal fluid (CSF). The method was used to simultaneously determine the concentrations of all analytes in a small sample volume (as little as 25 microL) of rat CSF. The lower limits of quantification (LLOQ) of the method are 0.04 ng/mL for DZP and 0.1 ng/mL for its metabolites. The calibration range is 0.04-200 ng/mL for DZP and 0.1-200 ng/ml for the metabolites. All intra- and inter-assay coefficients of variation (%CV) and mean percent errors of the method are less than 12%. This method successfully addresses the need to determine low therapeutic drug concentrations in small physiological samples, namely rat CSF. Moreover, it can be used to investigate the distribution of the drug and its metabolites among blood plasma, brain tissue, and CSF in pharmacokinetic and pharmacodynamic studies in a variety of laboratory animals. With respect to animal experiments involving assays in CSF, this method addresses two of the three criteria of Russell and Bruch (Principles of Humane Experimental Techniques, 1959, Methuen and Co., London) for minimizing animal use, namely refinement and reduction.

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“…So far only a few studies have been reported to successfully separate the four TOF conformers . Zsila et al.…”

Section: Introductionmentioning

confidence: 99%

“…So far only a few studies have been reported to successfully separate the four TOF conformers [6]. Zsila et al developed a method employing a Chiralcel OJ column using n-hexane, 2-propanol (IPA) and methanol (MeOH) (72:1.5:3, v/v/v) as a mobile phase to detect all four stereoisomer peaks, however, the low resolution values hindered their accurate quantification.…”

Section: Introductionmentioning

confidence: 99%

Enantiomeric quality control of R‐Tofisopam by HPLC using polysaccharide‐type chiral stationary phases in polar organic mode

et al. 2018

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A novel, fast and economic chiral HPLC method was developed and validated for the resolution of the four isomers of tofisopam. The separation capacity of eleven different chiral columns: six polysaccharide-type including three amylose-based (Chiralpak AD, Chiralpak AD-RH and Chiralpak AS) and three cellulose-based (Chiralcel OD, Chiralcel OJ and Lux Cellulose-4); three cyclodextrin- (Quest-BC, Quest-C2 and Quest-CM) and two macrocyclic glycopeptide antibiotic-type (Chirobiotic T and Chirobiotic TAG) were screened using polar organic or reversed-phase mode. Chiralpak AD, based on amylose tris(3,5-dimethylphenylcarbamate) as chiral selector with neat methanol was identified as the most promising system. In order to improve resolution, an orthogonal experimental design was employed, altering the concentration of 2-propanol, column temperature, and flow rate in a multivariate manner. Using the optimized method (85/15 v/v methanol/2-propanol, 40°C, flow rate: 0.7 mL/min) we were not only able to separate the four isomers but also detect 0.1% S-enantiomer as chiral impurity in R-tofisopam. This is important since the latter is under development as a single enantiomeric agent. Thermodynamic investigation revealed an unusual entropy and enthalpy-entropy co-driven controlled enantioseparation on Chiralcel OJ and on Chiralpak AD column, respectively. Our newly developed HPLC method was validated according to the ICH guidelines and its application was tested on a pharmaceutical formulation containing the racemic mixture of the drug. As a further novelty, a separate circular dichroism method was applied for the investigation of the interconversion kinetics of tofisopam conformers, which proved to be crucial for sample preparation and method validation.

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Chromatographic separation of 2,3-benzodiazepines

Cited by 10 publications

References 36 publications

Negative Allosteric Modulation of AMPA‐preferring Receptors by the Selective Isomer GYKI 53784 (LY303070), a Specific Non‐competitive AMPA Antagonist

Negative Allosteric Modulation of AMPA‐preferring Receptors by the Selective Isomer GYKI 53784 (LY303070), a Specific Non‐competitive AMPA Antagonist

Simple and sensitive liquid chromatography/tandem mass spectrometry method for the determination of diazepam and its major metabolites in rat cerebrospinal fluid

Enantiomeric quality control of R‐Tofisopam by HPLC using polysaccharide‐type chiral stationary phases in polar organic mode

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