Conformational recognition by central benzodiazepine receptors

Simonyi, Miklós; Maksay, Gábor; Kovács, I.; Tegyey, Zsuzsanna; Pa̋rkányi, László; Kàlmán, Alajos; Ötvös, László

doi:10.1016/0045-2068(90)90010-3

Cited by 26 publications

(19 citation statements)

References 16 publications

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“…DZP was docked using its assumed bioactive conformation as input for docking [62]–[66]. QM partial charges were calculated using Jaguar 7.6 default settings.…”

Section: Methodsmentioning

confidence: 99%

A Unified Model of the GABAA Receptor Comprising Agonist and Benzodiazepine Binding Sites

et al. 2013

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We present a full-length α1β2γ2 GABA receptor model optimized for agonists and benzodiazepine (BZD) allosteric modulators. We propose binding hypotheses for the agonists GABA, muscimol and THIP and for the allosteric modulator diazepam (DZP). The receptor model is primarily based on the glutamate-gated chloride channel (GluCl) from C. elegans and includes additional structural information from the prokaryotic ligand-gated ion channel ELIC in a few regions. Available mutational data of the binding sites are well explained by the model and the proposed ligand binding poses. We suggest a GABA binding mode similar to the binding mode of glutamate in the GluCl X-ray structure. Key interactions are predicted with residues α1R66, β2T202, α1T129, β2E155, β2Y205 and the backbone of β2S156. Muscimol is predicted to bind similarly, however, with minor differences rationalized with quantum mechanical energy calculations. Muscimol key interactions are predicted to be α1R66, β2T202, α1T129, β2E155, β2Y205 and β2F200. Furthermore, we argue that a water molecule could mediate further interactions between muscimol and the backbone of β2S156 and β2Y157. DZP is predicted to bind with interactions comparable to those of the agonists in the orthosteric site. The carbonyl group of DZP is predicted to interact with two threonines α1T206 and γ2T142, similar to the acidic moiety of GABA. The chlorine atom of DZP is placed near the important α1H101 and the N-methyl group near α1Y159, α1T206, and α1Y209. We present a binding mode of DZP in which the pending phenyl moiety of DZP is buried in the binding pocket and thus shielded from solvent exposure. Our full length GABAA receptor is made available as Model S1.

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“…DZP was docked using its assumed bioactive conformation as input for docking [62]–[66]. QM partial charges were calculated using Jaguar 7.6 default settings.…”

Section: Methodsmentioning

confidence: 99%

A Unified Model of the GABAA Receptor Comprising Agonist and Benzodiazepine Binding Sites

et al. 2013

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“…For the notation of the different conformers we use the characteristic torsion angle C2-C3-N4-C5 ( 2345 ) of the diazepine ring. 8 Hence, the sign of 2345 defines descriptors for conformation M (minus) and conformation P (plus). 8 Apart from the extensive experimental work devoted to 1,4-benzodiazepines, only a few investigations have been carried out using theoretical methods.…”

Section: Introductionmentioning

confidence: 99%

“…8 Hence, the sign of 2345 defines descriptors for conformation M (minus) and conformation P (plus). 8 Apart from the extensive experimental work devoted to 1,4-benzodiazepines, only a few investigations have been carried out using theoretical methods. [9][10][11][12] These studies were mainly restricted to the determination of the geometry and conformational space of 1,4-benzodiazepines using force field and semiempirical methodologies.…”

Section: Introductionmentioning

confidence: 99%

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Ring inversion barrier of diazepam and derivatives: Anab Initio study

Paizs

Simonyi

1999

Chirality

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“…Even in the absence of an asymmetric center, BDZs exist as conformational racemates. [15][16][17][18] For example, DZ and NDZ each exists in P (plus) and M (minus) conformations, which are mirror images of each other (Fig. 6).…”

Section: Conformationmentioning

confidence: 99%

Acid‐Catalyzed nucleophilic substitution and racemization of 3‐methoxy‐N‐desmethyldiazepam enantiomers in methanol

Yang

1993

Chirality

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ABSTRACTpK,, values of 3-methoxy-N-desmethyldiazepam in acetonitrile and methanol containing various acid concentrations were determined by spectrophotometry to be 3.5 and 1.3, respectively. Temperature-dependent racemization of enantiomeric 3-methoxy-Ndesmethyldiazepam in methanol containing 0.5 M H2S04 was studied by circular dichroism spectropolorimetry and the racemization reactions were found to follow apparent first-order kinetics. Thermodynamic parameters of the racemization reaction were found to be: E,,, = 18.8 kcal/mol, and at 25°C: AH* = 18.3 kcal/mol, AS* = -14.8 entropy unit, and AG* = 22.7 kcal/mol, respectively. The racemization had an isotope effect (lzH/kD) of 1.6 at 42°C. Based on the results of this report and those of earlier reports by other investigators, a nucleophilically solvated C3 carbocation intermediate resulting from either a P (plus) or an M (minus) conformation is proposed to be an intermediate and responsible for the stereoselective nucleoplulic substitution and the subsequent racemization of 3-methoxy-N-desmethyldiazepam enantiomers.o 1993 Wiey-Liss, Inc.KEY WORDS: 1,4-benzodiazepines, oxazepam, 3-O-methyloxazepam, stereoselective nucleophilic substitution, kinetics 3-Methoxy-N-desmethyldiazepam (3-MeO-NDZ) is a pharmacologically active derivative of oxazepam (OX); the latter is among the therapeutically used 1,4-benzodiazepines (BDZs) that have a hydroxyl group at the C3 position (see structure and numbering system in Fig. 1). OX is an active metabolite of diazepam (DZ), which is one of the most frequently prescribed drugs2 for the treatment of anxiety and insomnia, and an adjuvant for ane~thesia.~ Early studiesP7 on the acid-catalyzed methanolysis of optically active 3-camphoyloxy-NDZ, 3-hemisuccinyloxy-NDZ and its methyl esters, and methanolysis of (+)-3-MeO-NDZ and ethanolysis of (+)-3-O-ethyl-lorazepam [the (+)-enantiomer corresponds to the S-enantiomerI7v8 indicated that two different mechanisms are involved in the racemization of 3-acyloxy, 3-hydroxy, and 3-alkoxy derivatives of NDZ and DZ. Enantiomeric 3-acyloxy-BDZs were reported to undergo racemization in acidic aqueous solutions via an initial formation of an enantiomeric 3-OH-BDZ with retention of absolute configuration, followed by racemization through ring-chain tautomerism. Under anhydrous conditions, enantiomeric 3-acyloxy-BDZs were reported to undergo alcoholysis by multiple exchange of the alkoxy g r o u~.~ The exchange of the same alkoxy group was called either "identity reaction" or "degenerate nucleophilic exchange". 4-6 A rather complex mechanism involving two inversion steps was proposed to be involved in the acid-catalyzed methanolysis and racemization of (+)-3-hemisuccinyloxy-NDZ and (+)-3-MeO-NDZ. 5*6 The authors of these earlier reports initially ruled out the p~s s i b i l i t y ,~.~ but 0 1993 Wiley-Liss. Inc.later accepted the suggestion6 of a C3 carbocation intermediate responsible for the formation of racemic 3-MeO-NDZ in the methanolysis of an enantiomeric 3-acyloxy-NDZ. However, neither the obser...

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Conformational recognition by central benzodiazepine receptors

Cited by 26 publications

References 16 publications

A Unified Model of the GABAA Receptor Comprising Agonist and Benzodiazepine Binding Sites

A Unified Model of the GABAA Receptor Comprising Agonist and Benzodiazepine Binding Sites

Ring inversion barrier of diazepam and derivatives: Anab Initio study

Acid‐Catalyzed nucleophilic substitution and racemization of 3‐methoxy‐N‐desmethyldiazepam enantiomers in methanol

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