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At least 19 recordsLinked to original sources

PubMed1977

Double-blind cross-over clinical comparison of two 2'-chloro benzodiazepines: 7-chloro-5-(2-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one (chlordesmethyldiazepam) versus 7-chloro-5-(o-chlorophenyl)-1,3-dihydro-3-hydroxy-2H-1,4-benzodiazepin-2-one (lorazepam) in neurotic anxiety.

A group of 20 female neurotic inpatients has been treated with 7-chloro-5-(2-chlorophenyl)-1,3-dihydro-2H-1,4-benzodiazepin-2-one-(chlordesmethyldiazepan)- 7-chloro-5(o-chlorophenyl)-1,3-dihydro-3-hydroxy-2H-1,4-benzodiazepin-2-one (lorazepam) according to a double-blind cross-over design. For each drug clinical evaluations were performed by means of Hamilton's rating scale for anxiety states and of Overall and Gorham's brief psychiatric rating scale, at the beginning, after the first week and at the end of the two-week period of treatment, in opposite sequence. A statistically greater efficacy of chlordesmethyldiazepam in comparison to lorazepam was observed. Results are discussed with regard to benzodiazepine structure-activity relationships.

Adult↗

PubMed1992

1,5-Benzodiazepines. X. Dialkylamino substituted 1,5-benzodiazepine and [1,2,4]triazolo [4,3-a][1,5] benzodiazepine derivatives with inhibitory activity on PAF-induced platelet aggregation.

Novel 4-(dialkylamino) substituted (4, 5 c, 8) and 2,4-bis(dialkylamino) substituted (6) 1,5-benzodiazepine derivatives were synthesized. Both these new compounds and the substituted 4H-[1,2,4]triazolo[4,3-a][1,5]benzodiazepine-5-amines 2 a-h, recently described by us, were tested in vitro for their inhibitory activity on the PAF-induced aggregation of human platelets. Actually, bicyclic compounds 4 d, 5 c and tricyclic compounds 2 g, h showed a significant activity: in all them the dialkylamino substituent was the 4-(ethoxycarbonyl)-1-piperazinyl group. On the contrary, compounds 4 d, 5 c, 2 g,h showed practically no inhibitory activity when platelet aggregation was induced by ADP, A23187, or collagen.

Benzodiazepines↗

PubMedDate not supplied

Treatment of benzodiazepine overdose with flumazenil. The Flumazenil in Benzodiazepine Intoxication Multicenter Study Group.

Flumazenil, a specific benzodiazepine antagonist, was evaluated as adjunctive therapy in the management of benzodiazepine overdose. Thirteen emergency departments enrolled 326 patients in this double-blind, placebo-controlled trial; 162 patients were randomly allocated to receive flumazenil (maximum dose, 30 ml, providing 3 mg of flumazenil), and 164 were allocated to receive placebo (maximum dose, 30 ml). A successful response was the attainment of a score of 1 or 2 on the Clinical Global Impression Scale (CGIS), denoting a very much improved or much improved status, 10 minutes after the start of intravenous administration of the test drug. Among those patients whose drug screen revealed the presence of benzodiazepines, 75 (77%) of 97 patients given flumazenil and 13 (16%) of 83 given placebo attained such a response. The mean CGIS score at 10 minutes for benzodiazepine-positive patients treated with flumazenil was 1.95 versus 3.58 for those given placebo. As determined by the Neurobehavioral Assessment Scale, 61% of patients who initially responded became resedated; in these patients, the effect of flumazenil lasted a median of 90 minutes. At the investigator's discretion, patients who did not achieve a criterion response in the double-blind trial could receive open-label flumazenil, titrated as in the double-blind phase. Among the benzodiazepine-positive patients, 9 (53%) of 17 patients from the flumazenil group responded to the additional flumazenil, and 58 (81%) of patients previously given placebo responded. Safety was assessed in all 326 patients given the test drug. The most frequent adverse experiences after the administration of flumazenil were agitation (7%), vomiting (7%), abnormal crying (4%), and nausea (4%); these effects were observed with a lower frequency in the placebo group. Serious adverse experiences were reported in 4 patients; these included seizures and cardiac arrhythmias. Of the 3 patients with seizures, 2 had ingested large doses of cyclic antidepressants in addition to the benzodiazepine. The toxicology screen for 1 of the 2 showed 1900 ng/ml of amoxapine and 900 ng/ml of nortriptyline; the toxicology screen for the other, who also had ventricular tachycardia, showed 1928 ng/ml of loxapine and 301 ng/ml of amoxapine. The results of this study confirm published reports of the efficacy of flumazenil in reversing benzodiazepine-induced sedation in patients with benzodiazepine overdose. This was accomplished irrespective of the presence of coingested drugs. Flumazenil is not recommended for patients with serious cyclic antidepressant poisoning or those who use benzodiazepines therapeutically to control seizure disorders. When used as recommended, however, flumazenil has been shown to have an acceptable safety level.

Adolescent↗

PubMedDate not supplied

Mapping of benzodiazepine-like immunoreactivity in the rat brain as revealed by a monoclonal antibody to benzodiazepines.

A monoclonal antibody against benzodiazepines (21-7F9) was used to study the distribution of benzodiazepine-like immunoreactivity in the rat brain. Immunodensitometry in combination with image analysis were used for quantification. The results showed a ubiquitous distribution of benzodiazepine-like immunoreactivity throughout the brain. Very high levels of benzodiazepine-like immunoreactivity were found in the Purkinje cell layer of the cerebellum, in the primary olfactory cortex, in the stratum pyramidale of the hippocampus and in the mitral cell layer of the olfactory bulb. High densities of benzodiazepine-like immunoreactivity were found in the granule cell layer of the cerebellum, the pyramidal cell layer of the olfactory tubercle, the granule layer of the dentate gyrus, the arcuate nucleus of the hypothalamus, the mammillary bodies, the interstitial nucleus of Cajal and superficial grey layer of superior colliculus. The substantia nigra pars compacta, the islands of Calleja and layers II, III, V and VI of the cerebral cortex had moderate levels of benzodiazepine-like immunoreactivity. Lower densities were found in the internal granular layer and the external plexiform layer of the olfactory bulb, in the molecular layer of the dentate gyrus, in layers I and IV of the cerebral cortex, in the nucleus caudate-putamen and most of the thalamic nuclei. The lowest density of immunoreactivity was found in the globus pallidus, and the strata radiatum, oriens and lacunosum-moleculare of the hippocampus. The distribution of endogenous benzodiazepine-like immunoreactivity was compared with the distribution of the GABA/benzodiazepine receptor by using both immunocytochemistry and receptor autoradiography. Our studies have shown a clear mismatch between the localization of the benzodiazepine-like immunoreactivity and the GABA/benzodiazepine receptors.

Animals↗

PubMed1978

Benzodiazepine receptor binding: the interactions of some non-benzodiazepine drugs with specific [3H] diazepam binding to rat brain synaptosomal membranes.

The interaction of several non-benzodiazepine drugs with [3H] diazepam binding to benzodiazepine receptors in rat brain synaptosomal membranes was investigated. Baclofen, benzoctamine, hydroxyzine, chlorpromazine, haloperidol, imipramine, and amitriptyline displace specific [3H] diazepam binding, but the concentrations needed are too high to explain pharmacological effects of these drugs by an interaction with benzodiazepine receptors. The most potent non-benzodiazepine drug for inhibiting specific [3H] diazepam binding was methaqualone (IC50 value of 150 micrometer). It is suggested that interactions with benzodiazepine receptors may account for the anxiolytic and anticonvulsive side effects of this drug. The analeptic drug pentylenetetrazole interacts with benzodiazepine receptor binding with an IC50 value of about 1 mM, which is possibly too high to explain its convulsive properties by an antagonism at the benzodiazepine receptor.

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↗

PubMed1992

Biotinylated 1012-S conjugate as a probe ligand for benzodiazepine receptors: characterization of receptor binding sites and receptor assay for benzodiazepine drugs.

A nonisotopic receptor assay using the biotin-1012-S conjugate was developed and the usefulness of this conjugate as a probe ligand for the benzodiazepine receptor was evaluated. The conjugate was incubated in a receptor suspension, and then the concentration of free conjugate in the supernatant was determined nonisotopically with a solid-phase avidin-biotin binding assay. Studies on the ligand saturation with the conjugate demonstrated that the conjugate has very high affinity and specificity for the receptors and the biotin labeling does not decrease the affinity of 1012-S. This assay method was applied to the characterization of binding sites of benzodiazepine receptors in cow brain. Competition interactions between the conjugate and benzodiazepine drugs gave well-defined dose-response curves. These results confirm the possibility that this conjugate could serve as a probe for the study of receptor-ligand interactions and provide the basis of a new nonisotopic receptor assay for benzodiazepine drugs.

Animals↗

PubMed1991

Peripheral-type benzodiazepine receptors: a second site of action for benzodiazepines.

Benzodiazepines are among the most widely used therapeutic drugs because of their sedative and anxiolytic effects mediated through modulation of GABAA receptors. Another recognition site for these drugs, termed the peripheral-type (or mitochondrial) benzodiazepine receptor, is much more prevalent throughout the body for which a physiologic and pharmacologic role has just been found. This drug receptor plays a central role in the regulation of steroidogenesis by mediating the rate-limiting step in this biosynthetic pathway, which is transport of cholesterol to inner mitochondrial membranes. Although once considered by many to be an insignificant drug-binding site because a specific function remained elusive for many years, peripheral-type benzodiazepine receptors are now viewed with renewed interest because certain benzodiazepines such as diazepam may exert secondary effects on steroid production under appropriate physiologic conditions. Elucidation of this receptorial role should initiate new studies to examine in more detail the pharmacologic profile of drugs that bind to these sites and provides a novel target for the treatment of certain types of endocrine disorders.

Animals↗

PubMed1977

[Study of 1,5-benzodiazepines. II. Synthesis of 2,4-di-(N-alkyl,N-phenyl)amino-3H-1,5-benzodiazepine].

Following the procedure we described for synthesizing analogous compounds in Note I (7), reaction of N,N-dialkyl or (N-alkyl,N-phenyl)ethoxycarbonylacetamides with 4-chloro-1,2-phenylendiamine, in the presence of phosphorus oxychloride, afforded 2,3-dihydro-2-oxo-4-dialkyl (N-alkyl,N-phenyl)amino-chloro-1H-1,5-benzodiazepines. When a large amount of phosphorus oxychloride was employed in the reaction, the formation of 2,4-di-(N-alkyl,N-phenyl)amino-3H-1,5-benzodiazepines was achieved, starting from suitable o-phenylendiamines and (N-alkyl,N-phenyl)ethoxycarbonylacetamides. Pharmacological tests were carried out on some compounds described in the present paper and on others reported in the preceding Note (7); in this connection 4-amino-1,5-benzodiazepine derivatives showed weak CNS depressing activity in addition, in some cases, to clear, although moderate, anticonvulsant activity, whereas 2,4-diamino-1,5-benzodiazepine derivatives were practically without effect.

Animals↗

PubMedDate not supplied

Effects of the benzodiazepine receptor agonist midazolam and antagonist flumazenil on 5-hydroxytryptamine release from guinea-pig intestine in vitro. Indirect support for a "natural" benzodiazepine-like substance in the intestine.

Isolated segments of the guinea-pig small intestine and the guinea-pig stomach were vascularly perfused and the release of 5-hydroxytryptamine (5-HT) and 5-hydroxyindoleacetic acid into the portal venous effluent determined by high pressure liquid chromatography with electrochemical detection. Test substances were applied intraarterially. The benzodiazepine receptor agonist, midazolam, concentration-dependently increased (by 58%, at 1 nmol/l) and decreased (by 32%, at 100 nmol/l) the release of 5-HT from small intestine preparations. Both effects were blocked by the benzodiazepine receptor antagonist flumazenil (10 nmol/l) The stimulatory effect of midazolam was also abolished in the presence of tetrodotoxin (1 mumol/l) or scopolamine (100 nmol/l). In the absence of tetrodotoxin, flumazenil (10 nmol/l) alone decreased the release of 5-HT from the small intestine by 41%, but it increased the release of 5-HT by 50% in the presence of tetrodotoxin. Both effects of flumazenil were abolished in the presence of bicuculline (50 mumol/l). In the absence of tetrodotoxin, flumazenil (10 nmol/l) decreased also the release of 5-HT and its metabolite from the perfused stomach by about 40%, whereas midazolam (1 nmol/l) caused an increase by about 60%. In conclusion, benzodiazepine receptors modulate the previously described intrinsic GABAergic regulation of 5-HT release from enterochromaffin cells in the guinea-pig intestine. It is suggested that an endogenous benzodiazepine-like substance of non-neuronal origin is present in the small intestine and stomach of the guinea-pig.

Animals↗

PubMed1991

Prenatal benzodiazepine administration. II. Lorazepam exposure is associated with decreases in [35S]TBPS binding but not benzodiazepine binding.

Prenatal benzodiazepine exposure has been associated with neurobehavioral alterations in humans and animals. To determine effects of prenatal benzodiazepine exposure on binding at the benzodiazepine and t-butylbicyclophosphorothionate (TBPS) sites on the GABAA receptor in mature offspring, we treated mice with lorazepam, 2 mg/kg/day, during days 13-20 of gestation. Binding was assessed at 6 weeks of age. There were no differences among controls, vehicle- or lorazepam-exposed mice in benzodiazepine receptor binding determined in vivo or in vitro. However, receptor density for [35S]TBPS binding sites was decreased in lorazepam-exposed offspring compared to the other groups. These data are consistent with prior neurochemical results indicating decreased TBPS binding and GABAA receptor function in several systems.

Animals↗

PubMed1975

Synthesis and central nervous system effects of 8.9-dihydro(1)benzazepino(3,2.1-ak)(1,4)benzodiazepin-1(2H)-ones and (1) binzazepino(3,2,1-jk)(1,4)benzodiazepin-1(2H)-ones.

A series of 4-alkyl-8,9-dihydro[1]benzazepino[3,2,1-jk][1,4]benzodiazepin-1(2H)-ones and brominated derivatives was synthesized. Two approaches for the synthesis of 4-alkyl[1]benzazepino[3,2,1-jk][1,4]benzodiazepin-1(2H)-ones and brominated derivatives are described. All compounds were evaluated for CNS activity. None showed significant activity. The results obtained indicate that in the case of the 1,3-dihydro-5-phenyl-2H-1,4-benzodiazepin-2-one a phenyl group at the 1 position causes a fall in CNS activity not only when it is free but also when fused to the benzodiazepine system.

Animals↗

PubMed1992

Characteristics of the association of brotizolam, a thieno-triazolo diazepine derivative, with the benzodiazepine receptor: a selective and high affinity ligand of the central type I benzodiazepine receptor.

Characteristics of the association of brotizolam, a thieno-triazolo diazepine derivative, to central benzodiazepine receptors were examined. Brotizolam significantly displaced the [3H]flunitrazepam and [3H]beta-carboline carboxylate ethylester bindings to crude synaptic membrane from the rat brain. This agent had the highest affinity for benzodiazepine receptors in the cerebellum, and it was found to be 2.1 times that in the spinal cord. Furthermore, a low concentration of brotizolam potentiated the GABA-stimulated 36Cl- influx into membrane vesicles. In contrast, the bindings of [3H]8-hydroxy-2-(di-n-propylamino)tetralin to 5-hydroxytryptamine1A receptors and [3H]ketanserin to 5-hydroxytryptamine2 receptors were not affected by brotizolam. The present results suggest that brotizolam may be a selective and high affinity ligand for the type I central benzodiazepine receptor. The anxiolytic and hypnotic actions of brotizolam seem to be not due to the association with 5-hydroxytryptamine receptor, but due to the activation of the GABAA receptor complex. Furthermore, the present results suggest that the lower affinity of brotizolam to benzodiazepine receptors in the spinal cord than those in the cerebellum may be related to the low muscle relaxation action of this drug.

Animals↗

PubMed1992

Chronic benzodiazepine administration. X. Concurrent administration of the peripheral-type benzodiazepine ligand PK11195 attenuates chronic effects of lorazepam.

Chronic administration of benzodiazepine active at the tau-aminobutyric acidA receptor ("central" benzodiazepine sites) is associated with behavioral tolerance and receptor downregulation. Recent reports indicate possible interactions between central sites and benzodiazepines active at "peripheral-type" sites located primarily on non-neuronal cells. To evaluate these interactions during chronic administration, we treated mice with lorazepam for 1 to 14 days alone or in combination with the peripheral-type site ligand PK11195 [N-methyl-N-(methyl-1-propyl)chloro-2-phenyl-1-isoquinoline-3-carboxamid e]. Lorazepam was associated with tolerance at 7 days, but tolerance was not observed during concurrent administration of PK11195. Lorazepam was also associated with benzodiazepine receptor down-regulation in cortex and hippocampus at 7 days. With concurrent administration of PK11195, this effect remained in cortex but was absent in hippocampus. tau-Aminobutyric acid-dependent chloride uptake was reduced in both cortex and hippocampus with lorazepam, but not with concurrent lorazepam and PK11195. PK11195 administration alone did not affect behavior or neurochemical parameters, or did it alter brain lorazepam concentrations. These data indicate that concurrent PK11195 administration attenuates behavioral and neurochemical effects of chronic lorazepam administration.

Animals↗

PubMed1991

A rapid screening method for the assessment of benzodiazepine receptor-related physical dependence in mice. Evaluation of benzodiazepine-related agonists and partial agonists.

We have developed a model of benzodiazepine-type physical dependence in which mice were injected subcutaneously with the test compound on a fixed schedule (0800 and 1600 for 3 days, the PM dose = AM dose x 2). If tolerated, then a starting dose of 150 mg/kg/day was generally used initially and the dose was lowered to 15 and 1.5 mg/kg/day in subsequent assays if the higher doses were active in the test. Twenty-four hours after the last dose, the mice received an intravenous injection of flumazenil (2.5 mg/kg), and 5 min later they were tested for electroshock seizure thresholds by an up-down titration method. Flumazenil-precipitated withdrawal was manifested by a lowering of the mA seizure threshold. We have found that compounds with benzodiazepine agonist properties significantly lower these thresholds in a dose-related fashion. For example, the following compounds (lowest effective mg/kg/day dose) were active in this regard, chlordiazepoxide (150), diazepam (15), flurazepam (15), alprazolam (15), triazolam (15), midazolam (15), zopiclone (150), Ro 16-6028 (150), and Ro 17-1812 (150). In contrast, zolpidem (150), tracazolate (15), and CL 218872 (15) did not cause physical dependence by this criterion. This rapid and simple screening test may be readily used to predict the physical-dependence-inducing properties of compounds that act at the benzodiazepine receptor.

Animals↗

PubMed1979

[1,5-Benzodiazepines. III. Synthesis of 2,4-bisdialkylamino-3H-1,5-benzodiazepines].

Treatment of 2,3-dihydro-2-oxo-4-dialkylamino-1H-1,5-benzodiazepines with phosphorus pentasulfide afforded 2-thio derivatives which in turn gave the corresponding methylmercapto derivatives by reaction with sodium hydride and methyl iodide. By treating these compounds with dialkylamines the formation of 2,4-bisdialkylamino-3H-1,5-benzodiazepines was achieved. Pharmacological screening of some of the products indicated that the introduction of a second dialkylamino substituent into the 1,5-benzodiazepine molecule gave the compounds CNS excitant properties, while the initial monodialkylamino derivatives containing sulfur showed a CNS depressant activity.

Amphetamine↗

PubMed1992

Chronic treatment with a benzodiazepine agonist in vivo increases the actions of the benzodiazepine partial inverse agonist, FG7142, on the hippocampal slice in vitro.

We have shown previously that chronic treatment of mice with a benzodiazepine agonist, flurazepam, increased the pharmacological actions of the partial inverse agonist, FG7142. We have investigated the neurophysiological basis for this using extracellular recordings of evoked field potentials in area CA1 of isolated hippocampal slices. The slices were prepared 48 h after the end of the chronic in vivo treatment, a time when no evidence of residual benzodiazepine agonist activity was found in the CNS. During perfusion with standard Ringer solution, no significant differences were seen between the field potentials in slices from flurazepam-treated mice and those from control animals. When FG7142 was added to the perfusion medium there was an increase in the secondary discharges that followed the initial population spikes, and an increase in paired pulse potentiation. These increases were significantly greater in slices from flurazepam-treated mice, compared with controls. The results show that the effects of the partial inverse agonist, FG7142, on an isolated neuronal preparation, were increased by chronic administration of a benzodiazepine agonist in vivo. This effect is suggested to be due to a decrease in GABAergic inhibition.

Animals↗

PubMed1992

Differential development of tolerance to the depressant effects of benzodiazepine and non-benzodiazepine agonists at the omega (BZ) modulatory sites of GABAA receptors.

In a previous study, it was found that both the benzodiazepine hypnotic, midazolam, and the imidazopyridine hypnotic, zolpidem, which has selective affinity for a sub-population of omega (benzodiazepine, BZ) modulatory sites of GABA(A) receptors, produced similar decreases in rates of food-reinforced lever pressing in rats. However, during 10 days of repeated administration, marked tolerance developed to the depressant effect of midazolam but little tolerance developed with zolpidem. It was found in the present study that, with a within-subject design similar to that used previously, tolerance developed to the response rate-decreasing activity of the benzodiazepine, triazolam and the cyclopyrrolone, zopiclone but not to that of the triazolopyridazine, CL 218,872. In another experiment, using a between-groups design, tolerance developed to the effect of midazolam, even if the injections were not associated with daily test sessions, providing no evidence for a drug-environment interaction. The lack of tolerance to zolpidem was confirmed in two experiments. There was little indication of tolerance to the depressant effect of zolpidem, even after 19 days administration of daily doses, up to 30 mg/kg, a dose 10 times greater than that which completely suppressed responding. These results showed that the extent to which tolerance develops to the effects of drugs with affinity for omega (BZ) modulatory sites can show wide variations which may be related to differences in mechanisms of action.

Animals↗