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PubMed1994

Chronic benzodiazepine agonist treatment produces functional uncoupling of the gamma-aminobutyric acid-benzodiazepine receptor ionophore complex in cortical neurons.

We have investigated the effect of chronic flurazepam HCl treatment on the gamma-aminobutyric acid (GABA)A receptor complex in cultured mammalian cortical neurons. Chronic flurazepam (1-5 microM, for 1-10 days) treatment did not produce any changes in the morphological appearance or the cell protein content of cortical neurons. The basal binding of [3H]flunitrazepam, [3H] Ro15-1788, and [3H]Ro15-4513 was also not altered after the chronic treatment. However, chronic flurazepam treatment produced uncoupling between GABA and pentobarbital sites and the [3H]flunitrazepam binding site. The EC50 values of GABA and pentobarbital were not significantly altered after chronic flurazepam treatment; however, their Emax values were decreased by approximately 50%. The effect of chronic flurazepam treatment on the observed uncoupling was both time and concentration dependent. Furthermore, the binding of [3H]GABA and t-butylbicyclophosphoro[35S]thionate was also not altered by chronic flurazepam treatment. The effect of GABA on 36Cl influx was not altered after chronic flurazepam treatment; however, treatment significantly attenuated the ability of diazepam to enhance GABA-induced 36Cl influx. Chronic flurazepam-induced uncoupling and decreased diazepam efficacy were reversed by the concomitant presence of the benzodiazepine antagonist Ro15-1788, suggesting that these events are mediated via the benzodiazepine receptor site. Taken together, these results suggest that chronic benzodiazepine treatment produces uncoupling of GABA and pentobarbital sites from the benzodiazepine site and decreased coupling between the benzodiazepine site and GABA receptor-gated Cl- channels. The uncoupling and decreased efficacy may be due to an alteration in the levels of various alpha subunits and may be responsible for the tolerance associated with chronic benzodiazepine agonist treatment.

Animals↗
PubMed1990

Chronic benzodiazepine antagonist treatment and its withdrawal upregulates components of GABA-benzodiazepine receptor ionophore complex in cerebral cortex of rat.

Effect of chronic administration of benzodiazepine (BZ) receptor antagonist Ro 15-1788 (flumazenil) (4 mg/kg once daily for 14 days) treatment and its withdrawal on locomotor activity, body temperature, and the binding pattern of receptor ligands that bind to GABA-BZ receptor ionophore complex in different regions of the brain of the rat was studied. Ro 15-1788 (x 14 d) increased the specific binding of [3H]ethyl-8-fluoro-5-6-dihydro-5-methyl-6-oxo-4H- imidazo[1,5 alpha][1,4]benzodiazepine-3-carboxylate [( 3H]Ro 15-1788), [3H]ethyl-8-azido-5-6-dihydro-5-methyl-6-oxo-4H- imidazo[1,5 alpha][1,4]benzodiazepine-3-carboxylate [( 3H]Ro 15-4513), [3H]flunitrazepam, and [35S]t-butylbicyclophosphorothionate [( 35S]TBPS) in cerebral cortex, and this increase in binding remained upregulated during the drug withdrawal at 24 h. The binding of [3H]Ro 15-1788 was also found significantly increased in the hippocampus, but not in cerebellum and striatum. The chronic Ro 15-1788 treatment did not alter the specific binding of [3H]GABA. Rosenthal analysis of the saturation isotherms indicated that the observed upregulation in the binding pattern of [3H]Ro 15-1788 and [3H]Ro 15-4513 in the cerebral cortex was due to an increase in the binding capacity (Bmax). The receptor affinity (Kd) was not changed. The withdrawal of Ro 15-1788 following its chronic administration also enhanced locomotor activity. However, no apparent change in body temperature was observed either due to chronic treatment or withdrawal. These data indicate that chronic Ro 15-1788 treatment and its withdrawal may produce an upregulation of subunits which bind the positive (benzodiazepines), negative (inverse agonist), and neutral (antagonist) ligands of benzodiazepine receptor.(ABSTRACT TRUNCATED AT 250 WORDS)

Affinity Labels↗
PubMed1983

Benzodiazepine inhibition of adenosine uptake is not prevented by benzodiazepine antagonists.

Uptake of [3H]adenosine into rat cerebral cortex synaptosomes was studied. Hexobendine (10(-5) M) and the benzodiazepine agonists diazepam (10(-5) M) and flurazepam (10(-4) M) significantly inhibited this uptake, but only if the compounds were pre-incubated for 10 min in the case of the benzodiazepines. The benzodiazepine antagonists Ro15-1788 (10(-5) M) and CGS 8216 (10(-5) M) failed to reverse the action of benzodiazepine agonists or hexobendine on [3H]adenosine uptake. The results add weight to the view that inhibition of adenosine uptake processes by benzodiazepines do not contribute to their behavioural effects.

Adenosine↗
PubMed1984

Benzodiazepine receptor ligand actions on GABA responses. Benzodiazepines, CL 218872, zopiclone.

The effects on GABA (4-aminobutyric acid) responses of several benzodiazepine and nonbenzodiazepine benzodiazepine receptor ligands were examined using mouse spinal cord neurons in dissociated cell culture. Diazepam, clonazepam and nitrazepam enhanced GABA responses potently at low nanomolar concentrations. Diazepam and clonazepam were most potent with significant enhancement at 1 nM and peak enhancement of 80.7 and 50.2% at 10 nM respectively. Nitrazepam was least potent with no significant enhancement at 1 nM and enhancement of only 20.7% at 10 nM. The benzodiazepine antagonist, Ro 15-1788, blocked enhancement by diazepam but also weakly enhanced GABA responses at low micromolar concentrations, suggesting partial agonist activity. The convulsant benzodiazepine, Ro 5-4864, did not enhance GABA responses at any concentration tested but antagonized GABA responses at 1 microM and above. Diazepam shifted GABA dose-response curves to the left by decreasing the apparent KD but without altering the apparent Vmax (Lineweaver-Burk analysis). Two nonbenzodiazepine anxiolytic/anticonvulsants, CL 218872 and zopiclone, were weak enhancers of GABA responses at high nanomolar concentrations. These results with benzodiazepines, CL 218872 and zopiclone are consistent with their anxiolytic and anticonvulsant profile in vivo and with studies of their effects upon low affinity GABA binding in vitro.

Animals↗
PubMed1979

A synthetic non-benzodiazepine ligand for benzodiazepine receptors: a probe for investigating neuronal substrates of anxiety.

CL 218,872 is the first non-benzodiazepine to selectively displace brain specific 3H-diazepam binding with a potency comparable to that of the benzodiazepines. Like the benzodiazepines, CL 218,872 increased punished responding in a conflict situation and protected against the convulsions induced by pentylenetetrazole. These three pharmacological properties are highly predictive of anxiolytic activity. Unlike the benzodiazepines, however, CL 218,872 was relatively inactive in tests designed to measure effects on neuronal systems which utilize GABA, glycine and serotonin as transmitters. Furthmore, CL 218,872 was relatively free of the ataxic and depressant side effects commonly associated with the benzodiazepines. Because of this high degree of selectivity, CL 218,872 may represent a new probe for investigating neuronal substrates of anxiety.

Animals↗
PubMed1983

New concepts in benzodiazepine therapy: rebound anxiety and new indications for the more potent benzodiazepines.

Abrupt withdrawal of benzodiazepine treatment in generalized anxiety patients was found to induce a rebound anxiety state in addition to minor physical symptoms. Controlled clinical trials suggest that the newer high potency benzodiazepines (alprazolam, clonazepam and bromazepam) have novel psychiatric indications and greater anxiolytic effect than the classical benzodiazepines. Alprazolam, a triazolobenzodiazepine, was superior to placebo in the treatment of panic disorder, for which medium or low potency benzodiazepines are generally inefficacious. Clonazepam, an anticonvulsant which increases 5HT synthesis, was more efficacious than lithium in reducing manic symptoms. Bromazepam, a new potent benzodiazepine, was superior to diazepam in the treatment of generalized anxiety disorder.

Alprazolam↗
PubMed1983

Several new benzodiazepines selectively interact with a benzodiazepine receptor subtype.

The potency of several new benzodiazepines as inhibitors of [3H]flunitrazepam binding was investigated in membranes from rat cerebellum or hippocampus. It was found that quazepam and two of its metabolites have a higher affinity for benzodiazepine receptors in cerebellum than for those in hippocampus, indicating a preferential interaction of these compounds with BZ1-receptors. Other experiments indicated that these compounds have benzodiazepines agonistic properties similar to diazepam or flunitrazepam. Thus for the first time, benzodiazepines have been identified with differentially interact with different benzodiazepine receptors.

Animals↗
PubMed1993

Molecular requirement for anticonvulsant activity in a series of thiazolo-1,4-benzodiazepine derivatives and comparison with classical benzodiazepines.

1. The behavioural and anticonvulsant effects of several thiazolo[3,2-d][1,4]benzodiazepines (TBZ) were studied after intraperitoneal administration in DBA/2 mice, a strain genetically susceptible to sound-induced seizures. 2. Anticonvulsant effects on seizures evoked by means of auditory stimulation (109 dB, 12-16 kHz) were evaluated in DBA/2 mice placed singly under a perspex dome. 3. Hypothermic activity was observed after the highest doses of the benzodiazepines studied. 4. In addition, some TBZ were examined for anticonvulsant properties with respect to clonus induced by pentylenetetrazol. 5. Our study demonstrated that some thiazolobenzodiazepine derivatives were more potent than clobazam, desmethylclobazam and chlordiazepoxide, and less potent than diazepam, desmethyldiazepam and alprazolam. 6. In the series of tricyclic benzodiazepines, thiazole nucleus fusion to the "d" edge of the 7-membered ring results in an effective increase of the energy barrier for the heptatomic system reversal, and is probably responsible for, jointly with the lack of C=N double bonds, lower activity with respect to the 1,4-benzodiazepine precursors. 7. The potency of various thiazolobenzodiazepine derivatives as inhibitors of specific [3H]flunitrazepam binding to membranes from cerebellum or hippocampus was evaluated. 8. All tested compounds produced concentration-dependent inhibition of [3H]flunitrazepam binding. 9. The pharmacological activity of TBZ2, the most active compound of this series, was significantly reduced by treatment with flumazenil (2.5 mg/kg i.p.), suggesting clear involvement of a benzodiazepine mechanism in the anticonvulsant activity of these compounds.

Acoustic Stimulation↗
PubMed1984

Differential effects of the benzodiazepine antagonist Ro 15-1788 after "general anaesthetic" doses of benzodiazepines in mice.

The effects of the benzodiazepine antagonist Ro 15-1788 20 mg kg-1 after "general anaesthetic" doses of several benzodiazepines were studied in mice, in order to determine if the effects of the latter were attributable to an action at benzodiazepine receptors. Male CDI mice were used and the end-points for anaesthesia were loss of the righting reflex and loss of the foot pinch reflex. The effects of midazolam, and to a lesser extent those of chlordiazepoxide and of diazepam on these reflexes, were antagonized partially by Ro 15-1788. When the antagonist was given after high doses of flurazepam, convulsions were produced. Calculation of the likely membrane concentrations of the benzodiazepines showed that these fitted the lipid solubility correlation for general anaesthesia. Ro 15-1788 did not decrease the lethal effects of the benzodiazepines. With flurazepam, chlordiazepoxide and diazepam it caused signs of hyperexcitability, which in the case of flurazepam led to the death of the animals.

Anesthesia, General↗
PubMed1990

Addiction potential of benzodiazepines and non-benzodiazepine anxiolytics.

This paper reviews the addiction potential of all benzodiazepines currently available in the U.S.A. as well as several non-benzodiazepine anxiolytic drugs. Addiction potential was assessed by separately considering the potential for these drugs to produce three different phenomena of addiction; namely, physical dependence, psychological dependence and deleterious consequences. This review focuses on human studies conducted with research volunteers outside the therapeutic context and also on clinical studies conducted with patients receiving treatment in the therapeutic context. It is concluded that benzodiazepines have a reduced addiction potential in comparison to the predecessor barbiturates. Conclusions regarding the relative addiction potential of several non-benzodiazepine anxiolytics are difficult due to a paucity of data; however limited evidence suggests a reduced addiction potential for several of these compounds. Within the benzodiazepine class, qualitative differences in addiction potential between individual drugs are not well established.

Anti-Anxiety Agents↗
PubMed1989

Chronic benzodiazepine administration. III. Upregulation of gamma-aminobutyric acidA receptor binding and function associated with chronic benzodiazepine antagonist administration.

Chronic administration of a benzodiazepine agonist appears to downregulate benzodiazepine receptors and gamma-aminobutyric acid (GABA) receptor function. To examine the effects of chronic treatment with a benzodiazepine antagonist, we administered Ro15-1788, 1, 2 and 5 mg/kg/day to mice via implanted s.c. osmotic pumps for 1 to 14 days. Plasma and cortex (CX) concentrations of Ro15-1788 remained constant between days 1 and 7, indicating no change in pharmacokinetics. Open-field activity studies showed no change in distance traveled or ambulatory time at days 1, 2 and 4, but an increase in both parameters at days 7 and 14 in mice receiving Ro15-1788, 2 mg/kg/day. Benzodiazepine receptor binding was unchanged in CX, cerebellum (CB), hypothalamus, hippocampus and ponsmedulla at 1, 2 and 4 days at a dose of 2 mg/kg/day. Binding was increased in CX, CB and hippocampus at day 7 compared to days 1 and 2, and remained elevated at day 14. Similar results were observed at Ro15-1788 doses of 1 and 5 mg/kg/day. Benzodiazepine binding assessed in vitro in CX and CB also was increased at day 7 compared to day 1, due to an increase in receptor number rather than a change in apparent affinity. Binding of t-[35S]butylbicyclophosphorothionate to the chloride channel site in CX after Ro15-1788, 2 mg/kg/day, was increased at days 7 and 14 compared to days 1, 2 and 4 and controls due to an increase in number of binding sites. t-Butylbicyclophosphorothionate binding in CB was unchanged throughout.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1983

Quinazolines and 1,4-benzodiazepines. 92. Conformational recognition of the receptor by 1,4-benzodiazepines.

We propose that the conformation of 1,4-benzodiazepines that is recognized by the binding site on the benzodiazepine receptor complex is one in which the planes formed by the fused benzene ring and the methylene group (and the two adjoining atoms) of the diazepine ring are in the R configuration. The derivation of this conformation was based on comparisons of computer-generated 3-dimensional structures obtained from single-crystal X-ray data for diazepam, (R)- and (S)-1,3-dimethyl-5-(2-fluorophenyl)-7-nitro-1,3-dihydro-2H-1,4-benzodiazepin-2- one, and the structurally rigid ethyl (S)-7-chloro-11,12,13,13 alpha-tetrahydro-9-oxo-9H-imidazo[1,5-alpha] pyrrolo[2,1-d][1,4]benzodiazepine-1-carboxylate. The affinity of ligands for the benzodiazepine binding site was determined using the [3H]-diazepam binding assay.

Benzodiazepines↗
PubMed1988

The shark GABA-benzodiazepine receptor: further evidence for a not so late phylogenetic appearance of the benzodiazepine receptor.

Whilst the brain-specific benzodiazepine receptor has been assumed to show a late evolutionary appearance, we present evidence for the presence of a central benzodiazepine binding site in sharks, which shows a high affinity for [3H]Ro 15-1788. However, the receptor density and the affinities of several benzodiazepine receptor ligands are lower than in mammals, thus presumably explaining why the benzodiazepine binding sites had previously escaped detection in elasmobranchs. Additionally, radio- and immunohistochemistry were performed to localize the radioligand binding sites and the antigenic sites of the shark gamma-aminobutyric acid (GABA)-benzodiazepine receptor. In cerebellum, the granular layer reveals a high density of [3H]muscimol binding sites. The immunoreaction obtained with the beta-subunit-specific monoclonal antibody bd-17 seemingly parallels the distribution of high-affinity GABA binding sites. In contrast, [3H]Ro 15-1788 binding sites are evenly distributed in the molecular and granular layers, thus the results are similar to those previously described for rat cerebellum. Apparently, the respective distributions in this brain region are well conserved throughout vertebrate evolution.

Animals↗
PubMed1982

Contrasting regulation by GABA of the displacement of benzodiazepine antagonist binding by benzodiazepine agonists and purines.

Gaba increases the potency of the benzodiazepines chlordiazepoxide, clonazepam, diazepam, nitrazepam and oxazepam, and the triazolopyridazine CL 218,872 in displacing specific binding of the benzodiazepine antagonist [3H]Ro 15-1788. In contrast, the potencies of the purines 1-methyl- and 1-ethylisoguanosine for benzodiazepine antagonist binding sites were decreased by GABA, while the potencies of inosine, hypoxanthine, 6-dimethylaminopurine, and the non-benzodiazepine anxiolytic, zopiclone, were unaltered by GABA. The results suggest that the purines and 'classical' benzodiazepine agonists may bind to different conformations or populations of receptors.

Animals↗
PubMed2001

Chronic benzodiazepine use in general practice patients with depression: an evaluation of controlled treatment and taper-off: report on behalf of the Dutch Chronic Benzodiazepine Working Group.

BACKGROUND: Many patients with depression take benzodiazepine drugs long term despite the absence of continuing therapeutic value. AIMS: To evaluate a treatment programme involving gradual discontinuation with or without simultaneous selective serotonin reuptake inhibitor (SSRI) prescribing and to determine the long-term outcome after benzodiazepine withdrawal. METHOD: Patients went through three phases - change to an equivalent dose of diazepam; subsequent randomisation to either 20 mg of paroxetine or placebo; and gradual reduction of diazepam in depression-free patients - with a follow-up after 2 or 3 years. RESULTS: A total of 230 patients were recruited and 75% in the paroxetine group and 61% in the placebo group were successfully treated after 6 weeks (P:=0.067). After 2 or 3 years 13% of patients were still benzodiazepine free: 26% of those who had successfully tapered off benzodiazepine and 6% of the total group. CONCLUSIONS: Transfer to diazepam followed by gradual withdrawal is an effective way of discontinuing chronic benzodiazepine use. The addition of SSRI treatment is of limited value.

Adult↗
PubMed1988

Chronic benzodiazepine administration. I. Tolerance is associated with benzodiazepine receptor downregulation and decreased gamma-aminobutyric acidA receptor function.

Tolerance occurs to a number of the pharmacodynamic effects of benzodiazepines. To assess pharmacokinetic and neurochemical aspects of tolerance, lorazepam (LRZ) was administered chronically to mice via implantable osmotic pumps and rotarod ataxia, plasma and brain LRZ concentrations, benzodiazepine receptor binding in vivo and in vitro, chloride channel binding and muscimol-stimulated chloride uptake were examined in various brain regions over a 14-day period. Behavioral tolerance, indicated by diminished rotarod ataxia, developed at all doses examined (1, 2, 4 and 10 mg/kg/day), with little change occurring before day 4. The greatest decrease in rotarod ataxia occurred between days 4 and 7. Plasma and brain LRZ concentrations were proportional to dose and were constant over time at each dose, indicating that tolerance was not pharmacokinetic. Benzodiazepine receptor binding as determined by the specific uptake of [3H]Ro15-1788 decreased in cortex, hypothalamus and hippocampus primarily between days 4 and 7, with an approximately 50% decrement in each region by day 7. Receptor binding and rotarod ataxia in cortex were highly correlated at each dose. Apparent affinity in vivo at the receptor was unchanged in cortex, indicating that altered ligand uptake was due to decreased receptor number. Similar results were observed in membrane preparations. There was a small, nonsignificant decrease in chloride channel binding at day 7 compared to day 1. Muscimol-stimulated chloride uptake into cortical synaptoneurosomes was decreased at day 7 compared to day 1. Thus, downregulation of benzodiazepine receptor binding and of gamma-aminobutyric acidA receptor function is closely associated with behavioral tolerance to benzodiazepines.

Animals↗
PubMed1982

Limited in vivo bioassays on some benzodiazepines: lack of experimental initiating or promoting effect of the benzodiazepine tranquillizers diazepam, clorazepate, oxazepam and lorazepam.

Four benzodiazepine tranquillizers were tested for their ability to initiate or promote the development of preneoplastic and neoplastic rat liver lesions. In comparison with the liver carcinogen, N-2-fluorenylacetamide, the benzodiazepines exhibited no initiating activity during a 14-week period of daily administration by gavage. To study the promoting activity, N-2-fluorenylacetamide was used to initiate altered foci and neoplastic nodules in rat liver during 8 weeks and then the benzodiazepines were administered by daily gavage for a period of 12 weeks. The liver tumor promoter phenobarbital had a substantial enhancing effect upon the persistence of nodules but none of the benzodiazepines showed a similar effect. Thus, in the process model systems used, to detect initiating or promoting potential effect, the benzodiazepine tranquillizers failed to exhibit either an initiating or a promoting action.

2-Acetylaminofluorene↗
PubMed2006

5-aryl-imidazo[2,1-c][1,4]benzodiazepine derivatives as tricyclic constrained analogues of diazepam and Ro5-4864. Synthesis and binding properties at peripheral and central benzodiazepine receptors.

Four series of 5-aryl-imidazo[2,-c][1,4]benzodiazepine derivatives 1a-f, 2a-f, 3a-f, and 4a-f were synthesized and tested for their affinity at both the peripheral and central benzodiazepine receptors. Among the four series, only N-10 and C-11 sites were changed, mainly [N(CH3)-CO], [N=CH], [NH-CO], [NH-CH2], and in each series the halogen site was varied at the positions C-7, C-2', and C-4'. In particular, 10-methyl-benzodiazepinones 1a and 1b were designed as tricyclic constrained analogues of diazepam and Ro5-4864. All the tested compounds did not show significant binding activity at central benzodiazepine receptors, but relatively good PBzR binding affinities were found for 10-methyl-benzodiazepinone 1c and benzodiazepines 2b, c. Benzodiazepinones 3a-f were prepared by cyclization with 1,1'-carbonyldiimidazole of the corresponding 2-(aryl-imidazol-1-yl-methyl)-arylamines, obtained from the suitable (2-amino-aryl)-aryl-methanols with 1,1'-carbonyldiimidazole in different conditions. N-Alkylation of 3a-f to 1a-f was achieved using dimethylformamide-dimethylacetal. Reduction of 3a-f to 4a-f was accomplished with lithium aluminum hydride or borane and oxidation of 4a-f to 2a-f was performed with manganese (IV) oxide.

Adrenal Cortex↗