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PubMed2001

Behavioral effects of agents active at the gamma-aminobutyric acid receptor complex in the staircase paradigm.

This study examined the behavioral effects of agents active at the gamma-aminobutyric acid (GABA(A)) receptor complex in the mouse staircase paradigm. The neuroactivesteroids dehydroepiandrosterone (DHEA) and dehydroepiandrosterone sulfate (DHEA-S) were compared with the benzodiazepine agonist clonazepam, the non-benzodiazepine hypnotic compound zopiclone, and the antiepileptic agent gabapentin. Clonazepam, zopiclone and gabapentin reduced rearing activity at doses that did not affect climbing. The rearing-suppression effect of clonazepam and zopiclone, but not of gabapentin, was blocked by the benzodiazepine antagonist flumazenil, suggesting that the added effect of gabapentin is not mediated by the benzodiazepine receptor on the GABA complex. DHEA suppressed rearing behavior at doses that did not reduce climbing, but analysis with the Bonferroni post hoc test yielded no statistically significant difference. This inhibitory effect was attenuated by flumazenil. By contrast, DHEA-S suppressed, in a dose-dependent manner, both rearing and climbing behavior to the same extent. The findings support the potential value of the mouse staircase paradigm for demonstrating behaviorally relevant anxiolysis of test compounds shown to interact in vitro with the GABA(A) receptor complex.

Acetates↗

PubMed1986

Discriminative stimulus effects of atypical anxiolytics in baboons and rats.

Baboons and rats were trained to discriminate lorazepam and pentobarbital in a food-maintained two-lever drug vs. no-drug discrimination procedure. Previous research showed that benzodiazepines, but not barbiturates, occasioned drug lever responding in the lorazepam-trained animals. Lorazepam and six nonbenzodiazepines that have been proposed as anxiolytics (CGS 9896, CL 218,872, PK 9084, zopiclone, buspirone and 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol) were studied in test sessions in which responding on either level produced food. Of the nonbenzodiazepine compounds studied that displace 3H-benzodiazepines in vitro, CL 218,872 and zopiclone occasioned drug lever responding in all animals; PK 9084 did not occasion drug lever responding in any animal; and CGS 9896 did not occasion drug lever responding in lorazepam- or pentobarbital-trained baboons or in lorazepam-trained rats, but did so in the pentobarbital-trained rats. Buspirone, a nonbenzodiazepine anxiolytic with prominent dopaminergic activity, and 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol, a gamma-aminobutyric acid agonist, also did not occasion drug lever responding in either baboons or rats, regardless of training drug. Time course studies in baboons with CGS 9896, PK 9084, 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol and buspirone did not reveal delayed onset of drug stimulus generalization. Some differences in potency as a function of route of administration were found with CL 218,872, zopiclone and buspirone. The discriminative stimulus effects of lorazepam, CL 218,872 and zopiclone were antagonized by the benzodiazepine receptor antagonist Ro 15-1788. It is concluded that the discriminative stimulus properties of these nonbenzodiazepine compounds thus do not co-vary with their antipunishment effects, with their clinical efficacy as anxiolytics or with benzodiazepine receptor binding.

Animals↗

PubMed2006

The detection of sedatives in hair and nail samples using tandem LC-MS-MS.

Drug screening methods were developed to detect alprazolam, clobazam, clonazepam, diazepam, midazolam, oxazepam, temazepam, triazolam, zopiclone, and selected metabolites in human hair and nail samples employing liquid-liquid extraction and tandem liquid chromatography-mass spectrometry (LC-MS-MS). Hair and nail samples were obtained from patients who had recently discontinued or were currently prescribed one or more of the targeted drugs. Prazepam was used as the internal standard for all compounds. Some components in the hair matrix gave the same transitions as some of the analytes but did not compromise the analyses because their retention times differed from those for the target compounds. The analytical run time was 8-10min. Results of the hair analysis of a DFSA victim are also presented.

Adult↗

PubMed1983

Comparison of nitrazepam and zopiclone in psychiatric patients.

This investigation compares the effects of single and double doses of nitrazepam (5 and 10 mg) and zopiclone (7.5 and 15 mg) and placebo for 1 night in 40 psychiatric patients. The results indicate that zopiclone is an active hypnotic compound, comparable in its effects to those of nitrazepam, the higher dosage being best adapted to the type of patients included in the study.

Adolescent↗

PubMed1982

Comparison of nitrazepam and zopiclone in psychiatric patients.

Adolescent↗

PubMed2002

Role of the azinomycin naphthoate and central amide in sequence-dependent DNA alkylation and cytotoxicity of epoxide-bearing substructures.

Studies report a strong correlation between duplex DNA alkylation and in vitro cytotoxicity for a series of azinomycin partial structures 2-6 bearing the biologically relevant epoxide. Compounds lacking the naphthoate ester (e.g., 5 and 6) were poorly reactive toward DNA and were biologically inactive, as were compounds bearing the naphthoate but lacking the terminal carboxamide (e.g., 2). Compounds were evaluated for cytotoxicity against two breast cancer cell lines. [structure: see text]

Alkylation↗

PubMed2005

Design and synthesis of a DNA-crosslinking azinomycin analogue.

The azinomycins are potent antitumour antibiotics that are able to crosslink DNA, but are relatively unstable and unlikely to progress as therapeutic candidates. A prototype analogue 4 with more clinical potential has been designed and synthesised and incorporates the epoxide function of the azinomycins and a nitrogen mustard. Two further analogues 5 and 6 that can alkylate DNA but cannot crosslink the duplex have also been synthesised. Compound 4 crosslinks DNA efficiently at nM concentrations. Compounds 4-6 were submitted to the NCI 60 cell line screen and have similar antitumour activity, although 4 is slightly less active than the non-crosslinking compounds. These observations will be important in the design of further azinomycin analogues with antitumour activity.

Alkylation↗

PubMed2005

Validation of a liquid chromatography-tandem mass spectrometry method for the simultaneous determination of 26 benzodiazepines and metabolites, zolpidem and zopiclone, in blood, urine, and hair.

A liquid chromatography-tandem mass spectrometry method was developed for the simultaneous quantification of 26 benzodiazepines and metabolites, zolpidem and zopiclone, in blood, urine, and hair. Drugs were extracted from all matrices by liquid-liquid extraction with 1-chlorobutane. Chromatography was achieved using a XTerra MS C18 column eluted with a mixture of methanol and formate buffer. Data were acquired using positive electrospray ionization and multiple reaction monitoring using one precursor ion/product ion transition per compound. Quantification was performed using 13 deuterated analogues. Further confirmation of the identity of the compounds was achieved through a second injection of positive samples, monitoring two transitions per compound. The limits of quantification for all benzodiazepines ranged from 1 to 2 ng/mL in blood, 10 to 25 ng/mL in urine, and 0.5 to 10 pg/mg in hair. Linearity was observed from the limit of quantification of each compound to 200 ng/mL, 1000 ng/mL, and 1000 pg/mg for blood, urine, and hair, respectively (r2 > 0.99). Precision for quality control samples, spiked at three concentrations, was calculated (CV < 20% in most cases). Extraction recoveries for the three matrices ranged from 25.1 to 103.8%, except for one compound (cloxazolam in urine). Ion suppression was studied for all matrices. The validated assay was applied to authentic blood, urine, and hair samples from forensic cases.

Azabicyclo Compounds↗

PubMed1998

Design and synthesis of [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)-ethyl]phosphonic acid (EAA-090), a potent N-methyl-D-aspartate antagonist, via the use of 3-cyclobutene-1,2-dione as an achiral alpha-amino acid bioisostere.

The diazabicyclic amino acid phosphonate 15, [2-(8,9-dioxo-2,6-diazabicyclo[5.2.0]non-1(7)-en-2-yl)ethyl]phosphonic acid, was identified as a potent NMDA antagonist. It contains the alpha-amino acid bioisostere 3,4-diamino-3-cyclobutene-1,2-dione and an additional ring for conformational rigidity. Compound 15 was as potent as CGS-19755 (5) in the [3H]CPP binding assay, the stimulated [3H]TCP binding assay, and the NMDA-induced lethality model in mice. A single bolus dose of compound 15, administered intravenously following permanent occlusion of middle cerebral artery (MCA) in the rat, reduced the size of infarcted tissue by 57%. Structure-activity relationship (SAR) studies have indicated that the six- and eight-membered ring derivatives had diminished activity and that the two-carbon side chain length was optimum for NMDA receptor affinity. Substitution on the ring was found to be counterproductive in the case of sterically demanding dimethyl groups and of no consequence in the case of an H-bonding hydroxyl group. Replacement of the phosphonic acid group by either a carboxylic acid or a tetrazole group was unproductive. The potent bicyclic NMDA antagonists were synthesized efficiently by virture of their achiral nature and the ease of vinylgous amide formation from squaric acid esters. Compound 15, being a unique NMDA antagonist structural type with a favorable preclinical profile, may offer advantages over existing NMDA antagonists for the treatment of neurological disorders such as stroke and head trauma. Compound 15 is currently under clinical evaluation as a neuroprotective agent for stroke.

Animals↗

PubMed2001

Structure-antinociceptive activity studies of incarvillateine, a monoterpene alkaloid from Incarvillea sinensis.

Incarvillateine (1), a new monoterpene alkaloid carrying a characteristic cyclobutane ring, has been found to show significant antinociceptive activity in a formalin-induced pain model in mice. To investigate the correlation between its structure and antinociceptive activity, and especially to study whether a cyclobutane ring is necessary or not for expression of activity, we evaluated the antinociceptive activity of two constructive units of incarvillateine, such as a monoterpene unit (incarvilline, 3) and a phenylpropanoid unit (ferulic acid, 2) in the formalin test, and compared activity of the units with that of incarvillateine. Furthermore, in order to obtain more information about the structure-activity relationships, monoterpene alkaloid derivatives, such as incarvine C (5, a precursor of incarvillateine), incarvine A (4, an ester compound comprised of two monoterpene alkaloids and a monoterpene) and 3,3'-demethoxy-4,4'-dehydroxyincarvillateine (6, a synthetic new compound), were examined. The antinociceptive effect of 3,3'-demethoxy-4,4'-dehydroxyincarvillateine was equal to that of incarvillateine. Meanwhile, the other compounds exhibited no or weak activity. These results suggested that the cyclobutane moiety of incarvillateine plays an important role in expression of antinociceptive action.

Alkaloids↗

PubMedDate not supplied

Assessing the residual effects of hypnotics.

The therapeutic efficacy of a hypnotic can not be judged solely on its ability to induce and improve sleep. Many of the older compounds produce residual effects the next morning, such as impaired performance, lack of concentration and day-time sedation. This "hangover" phenomena will only serve to make the problem worse rather than better. The patient's quality of life would suffer, and this is particularly apparent in older patients. Zopiclone and zolpidem, two novel compounds, are superior to the older benzodiazepines in that they do not impair performance on tests of cognition, reaction time and memory the day following drug ingestion. These drugs may prove to be more beneficial and safer in people with sleep disorders who want to carry on with everyday life.

Aged↗

PubMed2003

[Drug treatment of sleep disorders in the elderly].

Changes in the pattern of sleep, e.g. more frequent nocturnal awakenings, are normal in the elderly. There is also a greater incidence of medical and psychiatric sleep disorders (depression, dementia). Initially, a thorough diagnostic assessment should be performed in order to identify disorders which can be treated specifically. For the symptomatic drug treatment of insomnias, the specific metabolic and pharmacokinetic, as well as possible interactions, should be considered. The new benzodiazepine receptor agonists (zopiclone, zolpidem and zaleplone), with their favourable risk-benefit profile, can be considered as first-choice treatments in elderly patients; in general, they should be preferred to the classical benzodiazepines. When a longer treatment is necessary, certain (non-anticholinergic) antidepressants and neuroleptics can be considered (the latter especially in cases of abnormal nocturnal behaviour). Herbal drugs and other hypnotically active compounds play a secondary role. Drug treatment of insomnia should always be carried out in the context of a general treatment plan which also includes non-pharmacological elements. In elderly patients, "chronotherapeutic" methods, which accentuate the sleep-wake rhythm, are of crucial importance.

Acetamides↗

PubMed2000

Effects of zolpidem and zopiclone on cognitive and attentional function in young healthy volunteers: an event-related potential study.

The effects of zolpidem and zopiclone, non-benzodiazepine ultra-short-acting hypnotics, on cognitive function and vigilance level were investigated in the morning following nocturnal administration using event-related potentials (ERP) and a sleep latency test (SLT). Zopiclone significantly shortened the sleep latency the following morning, whereas zolpidem did not, perhaps due to the difference in the elimination half-lives between the compounds. No significant effect was observed for either drug on the ERP indices, including the P3, mismatch negativity and negative difference components. At a clinically prescribed dosage these sleep inducers have no remarkable effect on cognitive or attentional functions but increase sleepiness of the subjects.

Adult↗

PubMed2000

Characterization of the interaction of zopiclone with gamma-aminobutyric acid type A receptors.

Zopiclone is a cyclopyrrolone that is used clinically as a hypnotic. Although this drug is known to interact with neuronal gamma-aminobutyric acid type A receptors, its binding site(s) within the receptor oligomer has been reported to be distinct from that of the classical benzodiazepines. After photoaffinity labeling with flunitrazepam, receptors in rat cerebellar membranes showed differentially reduced affinity for flunitrazepam and zopiclone by 50- and 3-fold, respectively. Because histidine 101 of the alpha-subunit is a major site of photolabeling, we have made specific substitutions of this residue and studied the consequences on the binding properties of zopiclone and diazepam using recombinant alpha1beta2gamma2-receptors transiently expressed in tsA201 cells. Both compounds showed similar binding profiles with receptors containing mutated alpha-subunits, suggesting a similar interaction with the residue at position 101. At alpha1beta2gamma3-receptors, flunitrazepam affinity was dramatically decreased by approximately 36-fold, whereas the affinity for zopiclone was decreased only 3-fold, suggesting a differential contribution of the gamma-subunit to the binding pocket. Additionally, we used electrophysiological techniques to examine the contribution of the gamma-subunit isoform in the receptor oligomer to ligand recognition using recombinant receptors expressed in Xenopus oocytes. Both compounds are agonists at alpha1beta2gamma2- and alpha1beta2gamma3-receptors, with flunitrazepam being more potent but less efficacious. In summary, these data suggest that histidine 101 of the alpha1-subunit plays a similar role in ligand recognition for zopiclone, diazepam, and flunitrazepam.

Amino Acid Substitution↗

PubMed1983

Pharmacokinetics and metabolism of zopiclone.

Pharmacokinetics and metabolism of a new hypnotic, zopiclone (ZD), were studied under the following conditions: (1) rats and dogs were given oral doses of the molecule, 14C-labeled either on the side chain or on the pyrrolopyrazine nucleus; (2) rats, rabbits and dogs were given increasing oral doses of the cold compound; (3) human subjects in various physiopathological situations--young and elderly healthy volunteers, patients with liver or renal impairments, nursing mothers--were given single or repeated doses, p.o. or i.v. (range 3.5-15 mg). ZD is rapidly and efficiently absorbed: its oral bioavailability was greater than 75% in all species except rats, where a first-pass effect of about 65% was recorded. Plasma protein binding is about 45%. The radioactive material rapidly diffuses from the vascular compartment, with a marked affinity for the brain. Plasma kinetics of ZD are generally well described by a two-compartment open model; in man, terminal half-life is 4-5 h; total body clearance is large (300 ml/mn), renal clearance very low (10 ml/min). The relationship between doses and concentrations, doses and urinary excretion of unchanged compound and major metabolites was linear in all species, except rabbits. The major metabolic routes involve decarboxylation affecting more than 50% of dose (rats and dogs), N-demethylation and N-oxidation--more than 30% as N-desmethyl and N-oxide derivatives in urine (humans). Due to intensive metabolism, only 7-10% of the dose is recovered in urine and feces as unchanged compounds (all species). In nursing mothers, milk and plasma kinetics of ZD are similar with a milk/plasma ratio around 0.80. In human volunteers, plasma half-life of ZD increases with age, while patients with liver or renal impairments show little or no modification of pharmacokinetic parameters.

Administration, Oral↗

PubMed1982

Pharmacokinetics and metabolism of zopiclone.

Pharmacokinetics and metabolism of a new hypnotic, zopiclone (ZD), were studied under the following conditions: (1) rats and dogs were given oral doses of the molecule, 14C-labeled either on the side chain or on the pyrrolopyrazine nucleus; (2) rats, rabbits and dogs were given increasing oral doses of the cold compound; (3) human subjects in various physiopathological situations - young and elderly healthy volunteers, patients with liver or renal impairments, nursing mothers - were given single or repeated doses, p.o. or i.v. (range 3.5-15 mg). ZD is rapidly and efficiently absorbed: its oral bioavailability was greater than 75% in all species except rats, where a first-pass effect of about 65% was recorded. Plasma protein binding is about 45%. The radioactive material rapidly diffuses from the vascular compartment, with a marked affinity for the brain. Plasma kinetics of ZD are generally well described by a two-compartment open model; in man, terminal half-life is 4-5 h; total body clearance is large (300 ml/mn), renal clearance very low (10 ml/min). The relationship between doses and concentrations, doses and urinary excretion of unchanged compound and major metabolites was linear in all species, except rabbits. The major metabolic routes involve decarboxylation affecting more than 50% of dose (rats and dogs), N-demethylation and N-oxidation - more than 30% as N-desmethyl and N-oxide derivatives in urine (humans). Due to intensive metabolism, only 7-10% of the dose is recovered in urine and feces as unchanged compounds (all species). In nursing mothers, milk and plasma kinetics of ZD are similar with a milk/plasma ratio around 0.80. In human volunteers, plasma half-life of ZD increases with age, while patients with liver or renal impairments show little or no modification of pharmacokinetic parameters.

Administration, Oral↗

PubMed2002

[Determination of zopiclone in serum by reversed-phase high performance liquid chromatography].

A reversed-phase high performance liquid chromatographic method (external standard method) was developed for the determination of zopiclone in serum. After the selective extraction with n-butyl chloride, this compound was chromatographed on a LiChroCART 125-4 column packed with LiChrospher 60 RP select B(5 microns) using acetonitrile-monopotassium phosphate (20:80, V/V) as mobile phase. The eluting compound was measured by an ultraviolet detector at 254 nm. Spiked with zopiclone of 400 micrograms/L, 1,600 micrograms/L and 6,400 micrograms/L in serum, the recoveries of zopiclone were (73.4 +/- 3.2)%, (82.2 +/- 4.1)% and (90.3 +/- 4.5)% respectively. The detection limit of the method was 15 micrograms/L. The method is simple and rapid for the determination of zopiclone in forensic toxicology.

Aged↗

PubMed1987

Simultaneous determination of zopiclone and its two major metabolites (N-oxide and N-desmethyl) in human biological fluids by reversed-phase high-performance liquid chromatography.

A high-performance liquid chromatographic method has been developed for the simultaneous determination of zopiclone and its main metabolites (N-oxide and N-desmethyl derivatives) in biological fluids. After selective extraction (dichloromethane-2-propanol) these compounds are chromatographed on a column packed with Spherisorb ODS-2 (5 micron) using monobasic sodium phosphate-methanol (45:55, v/v). The eluted compounds are measured by fluorescence detection. The limit of detection of the method is 5 ng/ml for zopiclone in plasma and urine and 10 ng/ml for its two main metabolites (coefficient of variation less than 10%). This method has been successfully applied to pharmacokinetic studies of zopiclone and its two main metabolites in healthy subjects and patients with chronic renal failure.

Adolescent↗