Dibenzo[1,2,5]thiadiazepines Are Non-Competitive GABAA Receptor Antagonists (original) (raw)
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molecules Dibenzo[1,2,5]thiadiazepines Are Non-Competitive GABA A Receptor Antagonists
A new process for obtaining dibenzo[c,f][1,2,5]thiadiazepines (DBTDs) and their effects on GABA A receptors of guinea pig myenteric neurons are described. Synthesis of DBTD derivatives began with two commercial aromatic compounds. An azide group was obtained after two sequential reactions, and the central ring was closed via a nitrene to obtain the tricyclic sulfonamides (DBTDs). Whole-cell recordings showed that DBTDs application did not affect the holding current but inhibited the currents induced by GABA (I GABA), which are mediated by GABA A receptors. These DBTDs effects reached their maximum 3 min after application and were: (i) reversible, (ii) concentration-dependent (with a rank order of potency of 2c = 2d > 2b), (iii) mediated by a non-competitive antagonism, and (iv) only observed when applied extracellularly. Picrotoxin (which binds in the channel mouth) and DBTDs effects were not modified when both substances were OPEN ACCESS Molecules 2013, 18 895 simultaneous applied. Our results indicate that DBTD acted on the extracellular domain of GABA A channels but independent of the picrotoxin, benzodiazepine, and GABA binding sites. DBTDs used here could be the initial model for synthesizing new GABA A receptor inhibitors with a potential to be used as antidotes for positive modulators of these receptors or to induce experimental epilepsy.
Modulation of GABAA receptor-mediated currents by phenazepam and its metabolites
2001
The effects of 7-bromo-5-(2-chlorophenyl)-1,3dihydro-2H-1,4-benzodiazepin-2-one (phenazepam, PNZ), a 1,4-benzodiazepine derivative, and its physiological metabolites on GABA-activated whole-cell currents were studied in enzymatically isolated rat Purkinje neurones. PNZ, its hydroxylated metabolite (HPNZ) and a reference benzodiazepine, diazepam, potently enhanced (up to 200% of control) peak amplitude of currents activated by 10 µM GABA with EC 50 s of 6.1±0.8, 10.3±1.4 and 13.5±1.9 nM respectively. Both PNZ and HPNZ caused a parallel leftwards shift of the concentration/effect relationship for GABA. Another metabolite, 6-bromo-(2-chlorophenyl) quinazoline-2-one (QNZ), augmented responses to 10 µM GABA with a maximal efficacy similar to that of the 1,4benzodiazepines tested, although its EC 50 was 2.4±0.2 µM. A further metabolite, 5-bromo-(2-chlorophenyl)-2-aminobenzophenone (ABPH), had only minimal effects on the responses elicited by 10 µM GABA. Incubation with QNZ and ABPH had biphasic effects on the concentration/effect relationship for GABA. These compounds enhanced peak amplitudes of currents activated by low concentrations of GABA, but inhibited responses to saturating concentrations of the agonist. This effect could, in part, be explained by the acceleration of the desensitisation process by those substances. It is concluded that both PNZ and HPNZ can be referred to as full positive modulators of GABA A receptors and that they are primarily responsible for GABAergic effects of therapeutic doses of PNZ.
Journal of Pharmacology and Experimental Therapeutics, 2006
Studies using mice with point mutations of GABA A receptor ␣ subunits suggest that the sedative and anxiolytic properties of 1,4-benzodiazepines are mediated, respectively, by GABA A receptors bearing the ␣ 1 and ␣ 2 subunits. This hypothesis predicts that a compound with high efficacy at GABA A receptors containing the ␣ 1 subunit would produce sedation, whereas an agonist acting at ␣ 2 subunit-containing receptors (with low or null efficacy at ␣ 1-containing receptors) would be anxioselective. Electrophysiological studies using recombinant GABA A receptors expressed in Xenopus oocytes indicate that maximal potentiation of GABA-stimulated currents by the pyrazolo-[1,5a]-pyrimidine, DOV 51892, at ␣ 1  2 ␥ 2S constructs of the GABA A receptor was significantly higher (148%) than diazepam. In contrast, DOV 51892 was considerably less efficacious and/or potent than diazepam in enhancing GABA-stimulated currents This work was done with either funding from (to P.
Journal of Medicinal Chemistry, 2005
A series of new 1,2-diphenylimidazole derivatives (1a-x) were synthesized and evaluated for their ability to potentiate γ-aminobutyric acid (GABA)-evoked currents in Xenopus laevis oocytes expressing recombinant human GABA A receptors. Many of these compounds enhanced GABA action with potencies (EC 50) 0.19-19 µM) and efficacies (maximal efficacies of up to 640%) similar to or greater than those of anesthetics such as etomidate, propofol, and alphaxalone. Structure-activity relationship analysis revealed that the presence of an ester moiety in the imidazole ring was required for full agonist properties, while modifications made in the phenyl rings affected potency and efficacy, with ethyl 2-(4-bromophenyl)-1-(2,4-dichlorophenyl)-1H-4-imidazolecarboxylate showing the highest potency. These compounds potentiated the [ 3 H]-GABA binding to rat brain membranes, suggesting a site of interaction different from that of GABA. As for etomidate, mutation of asparagine-265 in the 2 subunit of the GABA A receptor into serine reduced the ability of derivative 1i to modulate the GABA function.
Journal of Medicinal Chemistry, 1995
The syntheses of a series of novel imidazobenzodiazepines and their affinities for diazepam sensitive (DS) and diazepam insensitive (DI) GABAA receptors are described. Imidazobenzodiazepines belong to one of the very few chemical families which exhibit high to moderate potency for DI GABAA receptors. Although imidazobenzodiazepines such as Ro 20, are the most potent DI GABAA receptor ligands described to date, their selectivity for DI versus DS GABAA receptors is only marginal. Previous structure-activity relationship (SAR) studies of imidazobenzodiazepines have indicated that the 3and 8-positions are critical for highaffinity binding to DI GABAA receptors (to determine why the ester function is critical to high affinity at the DI site, we have synthesized several derivatives which have substituents other than an ester at the C(3) position including 3-alkyl-, 3-alkylketo-, 3-alkyl ether, and 3-dialkylamino-substituted imidazobenzodiazepines. The S A R analysis of these compounds when combined with that of several pyrazoloquinolinones indicates that interactions at H1 and L1 as well as interactions at H2 anti to the imidazole N(2) and at a lipophilic pocket (labeled LDi) about the 3-position are required in order for imidazobenzodiazepines to exhibit selectivity and high affinity for DI GABAA receptors. Furthermore, the imidazobenzodiazepines substituted with an electron-donating group (alkoxy function) at position 8 revealed that the change of the substituent at C(8) from an electron-withdrawing to a donating function did not substantially alter either ligand affinity or selectivity for DI GABAA receptors. Thus, a pharmacophore is proposed for DI GABAA receptor ligands, which is characterized by the requirement of a lipophilic pocket LDi about the C(3) position of imidazobenzodiazepines. Using this model, two pyrazoloquinolinone derivatives were designed and synthesized. Their affinities and selectivities for DI GABAA receptors are consistent with those predicted by the DI GABAA receptor pharmacophore. In addition, examination of the in vitro binding data of 3-alkyl ether analogs confirms that the anti conformation of the ester group at the C(3) position of imidazobenzodiazepines (Ro15-4513, 20 series) is preferred at both DI and DS GABAA receptors. This constitutes the first evidence (other than molecular modeling) to support the auxillary involvement of H2 at the DI site and is important with regard to the synthesis of other DI GABAA receptor selective ligands in the future. Comparison of the included volume developed here for the DI site vs the included volume for the DS site clearly demonstrates that the DI site is a smaller (subsite) binding cleft than the DS site and is clearly devoid of most of lipophilic area L3 ).
Tricyclic pyridones as functionally selective human GABAAα2/3 receptor-ion channel ligands
Bioorganic & Medicinal Chemistry Letters, 2004
A series of tricyclic pyridones has been evaluated as benzodiazepine site ligands with functional selectivity for the a 3 over the a 1 containing subtype of the human GABA A receptor ion channel. This investigation led to the identification of a high affinity, functionally selective, orally bioavailable benzodiazepine site ligand that demonstrated activity in rodent anxiolysis models and reduced sedation relative to diazepam. # 2004 Elsevier Ltd. All rights reserved.
The modulatory effects of the anxiolytic etifoxine on GABAA receptors are mediated by the β subunit
Neuropharmacology, 2003
The anxiolytic compound etifoxine (2-ethylamino-6-chloro-4-methyl-4-phenyl-4H-3,1-benzoxazine hydrochloride) potentiates GABA A receptor function in cultured neurons (Neuropharmacology 39 (2000) 1523). However, the molecular mechanisms underlying these effects are not known. In this study, we have determined the influence of GABA A receptor subunit composition on the effects of etifoxine, using recombinant murine GABA A receptors expressed in Xenopus oocytes. Basal chloride currents mediated by homomeric β receptors were reduced by micromolar concentrations of etifoxine, showing that β subunits possess a binding site for this modulator. In oocytes expressing α 1 β x GABA A receptors (x = 1, 2 or 3), etifoxine evoked a chloride current in the absence of GABA and enhanced GABA (EC10)-activated currents, in a dose-dependent manner. Potentiating effects were also observed with α 2 β x , β x γ 2s or α 1 β x γ 2s combinations. The extent of potentiation was clearly β-subunit-dependent, being more pronounced at receptors containing a β 2 or a β 3 subunit than at receptors incorporating a β 1 subunit. The mutation of Asn 289 in the channel domain of β 2 to a serine (the homologous residue in β 1) did not significantly depress the effects of etifoxine at α 1 β 2 receptors. This specific pattern of inhibition/potentiation was compared with that of other known modulators of GABA A receptor function like benzodiazepines, neurosteroids, barbiturates or loreclezole.
FEBS Letters, 1992
Chlordiazepoxide (CDPX) enhanced the rate of chloride exchange mediated by the major GABAA receptor found on sealed native membrane vesicles from rat cerebral cortex. The initial rate constant for chloride exchange for this receptor, (JA), a measure of open channel, was determined from the progress of GABA‐mediated influx of 36Cl−. The dependence of JA on GABA concentration was hyperbolic in the presence of CDPX (150 μM, sufficient to give maximum enhancement of chloride exchange rate) but sigmoid in its absence. Enhancement of channel opening (10‐fold at 0.3 μM GABA) decreased with increasing GABA concentration. The maximal response, above 1,000 μM GABA, was unaltered. The half‐response concentration was reduced from 80 μM to 50 μM. CDPX alone caused no measurable 36Cl− exchange. In the presence of CDPX, channel opening occurred with only one bound GABA molecule, whereas in its absence, channel opening with two bound GABA molecules was much more favorable. This could not be direct ...
Mol Pharmacol, 2006
Benz [e]indenes are tricyclic analogues of neuroactive steroids and can be modulators of GABA A receptor activity. We have examined the mechanisms of action of a benz[e]indene compound [3S-(3α,3aα,5aβ,7β,9aα,9bβ)]-dodecahydro-7-(2hydroxyethyl)-3a-methyl-1H-benz[e]indene-3-carbonitrile (BI-2) using single-channel patch clamp and whole-cell recordings from HEK cells transfected with rat GABA A receptor α1, β2, γ2L subunits. The data demonstrate that BI-2 is a positive modulator of GABA A receptor activity with a peak effect at 2 µM. The mechanism of modulation is similar but not identical to that of neuroactive steroids. Similar to steroids, BI-2 acts by prolonging the mean open time duration through an effect on the duration and prevalence of the longest open time component. However, in contrast to many steroids, BI-2 does not selectively reduce the channel closing rate. The potentiating action of BI-2 appears to be mediated through interactions with the classical neuroactive steroid binding site.