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At least 19 recordsLinked to original sources
PubMed1994

Synthesis and structure-activity relationships of 2,3-dihydrobenzofuran-7-carboxamide derivatives as potent serotonin-3 (5-HT3) receptor antagonists.

A series of N-(azabicyclo-3-yl)-2,3-dihydrobenzofuran-7-carboxamide derivatives were synthesized and evaluated for serotonin-3 (5-HT3) receptor antagonistic activities assessed by 5-HT3 receptor binding (in vitro) and by the ability to antagonize the von Bezold-Jarisch reflex in rats (in vivo). In these compounds, 1-azabicyclo[2.2.2]oct-3-yl derivatives were more potent than 8-methyl-8-azabicyclo[3.2.1]oct-3-yl derivatives for 5-HT3 receptor antagonistic activities. The introduction of methyl groups at position 2 of the dihydrobenzofuran ring increased the pharmacological activities (dimethyl > monomethyl > dihydro). Furthermore, the stereoisomers of dimethyl-, monomethyl-, and dihydrobenzofuran derivatives were prepared to evaluate the stereoselectivity of their 5-HT3 receptor binding affinities. Concerning the basic part, the compounds bearing (S)-1-azabicyclo[2.2.2]octan-3-yl moiety were more potent than their counterparts. With respect to the methyl substituent at position 2 of the dihydrobenzofuran ring, the rank order of the potency was dimethyl > or = (2S)-methyl > (2R)-methyl > dihydro. These results suggest that the (2S)-methyl group of the dihydrobenzofuran part contributes to the enhancement of the pharmacological activity. Among these compounds, (S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-5-chloro-2,3-dihydro-2,2- dimethylbenzofuran-7-carboxamide hydrochloride (24) showed the highest affinity for 5-HT3 receptors (Ki = 0.055 nM), and the most potent antagonistic activity on the von Bezold-Jarisch reflex (ED50 = 0.18 microgram/kg i.v.).

Animals↗
PubMed2000

Comparison of the effects of zolpidem and zopiclone on nocturnal sleep and sleep latency in the morning: a cross-over study in healthy young volunteers.

Zolpidem (ZOL) and zopiclone (ZPC) are non-benzodiazepine hypnotics, with unique effects on sleep architecture compared with conventional benzodiazepines. The two compounds have different profiles in action to two major subtypes of the GABA-A receptors, therefore different effects on sleep structure may be expected. In the present study, the effects of ZOL (10mg) and ZPC (7.5mg) were compared in nine healthy young male subjects during nine-night sessions, employing a crossover design. Time courses during the sessions were significantly different between the compounds in the ratio (%) of S2 and S1. Compared to the baseline, an increase of S2 and a decrease of S1 and SR were caused by ZPC, not by ZOL. SWS was increased by both ZPC and ZOL. Significant changes by ZOL were found during the first 150-min, while changes by ZPC were mostly observed during the second 150-min. This might be related to their half-lives. ZOL did not affect sleep latency in the morning, while ZPC caused a significant decrease. Subjective sleepiness, however, was not increased in the ZPC or ZOL mornings. It was speculated that difference in the action to the GABA-A receptor subtypes might be related to the differences in the effects on the sleep architecture between the compounds.

Adult↗
PubMed1984

5-Aryl-3-azabicyclo[3.2.0]heptan-6-one ketals, compounds with morphine-like analgesic activity.

A series of 5-aryl-3-azabicyclo[3.2.0] heptan -6-one ketals 6 were synthesized by hydride reduction of 1-aryl-4, 4-dimethoxy-1,2- cyclobutanedicarboximides 5. Imides 5 were obtained as the sole, regioselective products of the [2 + 2] photocycloaddition of 1,1- dimethoxyethylene to 2- arylmaleimides . The m-methoxyphenyl-N-methyl analogue 6a was demethylated to phenol 7 with EtSNa -DMF. Both 6a and 7 were similar to morphine in analgesic potency in rats and mice and showed physiological effects that were identical with those of morphine and that were completely reversed by naloxone. Compound 7 was identical with morphine in its ability to displace [3H]naloxone from homogenates of rat brain minus cerebellum. A molecular mechanics analysis of the m-methoxyphenyl analogue 6a showed that the nitrogen atom, the methoxyphenyl group, and the methoxyl oxygen cis to the phenyl group can be superimposed on the corresponding features of the morphine molecule, and perhaps this accounts for the observed opiate-receptor binding properties of 7.

Analgesia↗
PubMed1997

The effects of new hypnotic drugs in rats trained to discriminate ethanol.

Several new, non-benzodiazepine hypnotic drugs have recently been marketed (zopiclone, zolpidem) or are in development (zaleplon, SX 3228). These compounds act at benzodiazepine (BZ) (omega) receptors but have mechanisms of action which are not identical to those of benzodiazepines; in particular, zolpidem, zaleplon and SX 3228 have been reported to have selectivity for the BZ1 (omega 1) receptor subtype. In the present study the effects of the four hypnotic drugs were investigated in rats trained to discriminate ethanol (1 g/kg). Comparisons were made with pentobarbital and the benzodiazepines, lorazepam and midazolam. The two benzodiazepines and the barbiturate produced dose-related substitution for ethanol. In contrast, zolpidem, zaleplon, SX 3228 and zopiclone gave rise to only partial (maximum effect 50-67%) substitution, even at doses which greatly reduced rates of lever pressing. The limited ethanol-like effects of zolpidem, zaleplon and SX 3228 may be related to the more selective mechanism of action of these compounds. It is not clear why the effects of zopiclone differed from those of the benzodiazepines.

Acetamides↗
PubMed2002

Stereoselective discriminative stimulus effects of zopiclone in rhesus monkeys.

RATIONALE: The behavioral effects of racemic zopiclone are similar to those of benzodiazepines that positively modulate GABA at the GABA(A) receptor complex; however, it is not clear how enantiomers or metabolites of zopiclone contribute to the benzodiazepine-like behavioral effects of racemic zopiclone. OBJECTIVES: Racemic zopiclone, its ( R)- and ( S)- enantiomers, and the ( S)-N-desmethyl metabolite, were evaluated for discriminative stimulus effects in untreated and diazepam treated rhesus monkeys. METHODS: One group of monkeys discriminated the benzodiazepine midazolam and another group, treated daily with the benzodiazepine diazepam (5.6 mg/kg, PO), discriminated the benzodiazepine antagonist flumazenil. RESULTS: ( RS)-Zopiclone (0.32-17.8 mg/kg) and ( S)-zopiclone (0.1-10 mg/kg) substituted with similar potencies for midazolam (>/=80% midazolam-appropriate responding). The midazolam-like discriminative stimulus effects of ( RS)-zopiclone were antagonized by flumazenil (p K(B)=7.52). ( R)-Zopiclone occasioned a maximum 45% midazolam-appropriate responding at a dose of 100 mg/kg; ( S)-desmethylzopiclone produced saline-appropriate responding up to a dose of 100 mg/kg. All four test compounds occasioned predominantly vehicle-appropriate responding in diazepam treated monkeys discriminating flumazenil. ( RS)-Zopiclone (10 mg/kg) attenuated the discriminative stimulus effects of flumazenil in diazepam treated monkeys. CONCLUSIONS: These results clearly demonstrate that in rhesus monkeys the discriminative stimulus effects of zopiclone are stereoselective and qualitatively similar to those of midazolam. These results fail to show any benzodiazepine-like or benzodiazepine antagonist-like discriminative stimulus effects for ( S)- N-desmethylzopiclone, suggesting that any behavioral (e.g. anxiolytic) effects of this compound are not the result of actions at benzodiazepine receptors.

Administration, Oral↗
PubMed1996

Simultaneous determination of zolpidem and zopiclone in human plasma by gas chromatography-nitrogen-phosphorus detection.

A simple, specific and selective method for the simultaneous determination of zolpidem and zopiclone in human plasma is described. After a liquid-liquid extraction, the extract is injected into a capillary gas chromatograph with an OV-1 fused-silica column coupled to a nitrogen-phosphorus detector. The detection limits are 1 and 2 ng/ml for zolpidem and zopiclone, respectively. The method described is reproducible and linear over a range of concentrations, rendering it suitable for use for pharmacokinetic studies or toxicological evaluations. Absolute identification of the chromatographed compounds is accomplished by gas chromatography--mass spectrometry in both electron-impact and positive-ion chemical ionisation modes.

Artifacts↗
PubMed1998

Limited anxiolytic-like effects of non-benzodiazepine hypnotics in rodents.

The present experiments compared the anxiolytic-like effects of the benzodiazepine (BZD) hypnotic triazolam with those of four non-BZD hypnotics including one non-selective (zopiclone) and three omega1-BZD selective (zolpidem, zaleplon and SX-3228) receptor ligands, in classical animal models including conflict tests (punished lever pressing and punished drinking tests in rats) and exploratory models (elevated plus-maze test in rats and light/dark choice test in mice), and a recently developed mouse defence test battery (MDTB) which has been validated for the screening of anxiolytic drugs. Results from both conflict procedures showed that zopiclone (0.3-10 mg/kg) produced anxiolytic-like effects comparable to those of triazolam (0.1-3 mg/kg), whereas the selective omega1-BZD receptor hypnotics zolpidem (0.3-3 mg/kg), zaleplon (0.1-3 mg/kg) and SX-3228 (0.1-1 mg/kg) displayed weaker and/or non-specific anxiolytic-like effects. Similarly, in the light/dark test in mice, zolpidem (0.1-1 mg/kg), zaleplon (0.3-10 mg/kg) and SX-3228 (0.03-0.3 mg/kg) showed a reduced potential to produce anxiolytic-like effects as compared to the non-selective omega-BZD receptor hypnotics triazolam (0.03-1 mg/kg) and zopiclone (1-30 mg/kg). In the elevated plus-maze test, zopiclone (1-10 mg/kg), zolpidem (0.1-1 mg/kg), zaleplon (0.3-3 mg/kg) and SX-3228 (0.1-1 mg/kg) displayed anxiolytic-like activity at doses close to those producing behavioural impairment, whereas triazolam (0.03-1 mg/kg) exhibited anxiolytic-like effects over a wide dose range in the absence of decreases in general activity. In the MDTB, zaleplon (0.3-10 mg/kg) decreased all defensive responses, a profile which was similar to that of triazolam (0.03-1 mg/kg), while zopiclone (1-30 mg/kg), zolpidem (0.3-10 mg/kg) and SX-3228 (0.03-1 mg/kg) had fewer effects on defensive behaviours with several effects occurring only at motor-impairing doses. Taken together, these results demonstrate that, although selective omega1-BZD receptor hypnotics display anxiolytic-like activity, the effects are generally weaker than those observed with non-selective omega-BZD receptor selective hypnotics such as triazolam or zopiclone. In particular, the anxiety-reducing potential of the omega1-BZD receptor selective compounds is limited to certain anxiety measures and may be confounded and/or masked by behavioural suppression.

Acetamides↗
PubMed1985

Pharmacologic studies of central actions of zopiclone: influence on brain monoamines in rats under stressful condition.

In order to investigate the central action of zopiclone, the rat brain was divided into 8 regions and the changes in monoamines (MA) in each region were examined. The effect of zopiclone on stress was also examined from changes in brain monoamines under electro-footshock stress load in comparison with that of nitrazepam and flurazepam. The animals were decapitated at 1 h after administration of zopiclone, nitrazepam and flurazepam at each dose of 1 and 10 mg/kg (p.o.). No changes in MA at each region of the brain were noted, but the metabolite, homovanillic acid (HVA) was reduced at the cortex, hippocampus, hypothalamus and cerebellum. 5-hydroxyindoleacetic acid (5-HIAA) was reduced at the amygdala. Noradrenaline (NA) turnover accelerated by electro-footshock stress load was inhibited by zopiclone. From the results of this experiment, it was found that the effects of zopiclone on brain MA were similar to those of nitrazepam and flurazepam: inhibition of 5-HT turnover at the amygdala was common to these three compounds. This result suggests that zopiclone has similar pharmacological properties to benzodiazepines as an antianxiety agent.

Amygdala↗
PubMed2000

Effect of zopiclone and temazepam on sleep EEG parameters, psychomotor and memory functions in healthy elderly volunteers.

RATIONALE: The increased prevalence of sleep disturbance in old age is accompanied by a higher prescription rate of hypnotics, predominantly benzodiazepines in the elderly. In young volunteers zopiclone exerts a beneficial effect on sleep continuity without suppression of SWS and REM sleep; psychomotor performance and vigilance seemed to be less impaired than under classical benzoediazepines. OBJECTIVE: The present study investigates the effects of zopiclone on sleep EEG and cognitive performance in comparison to temazepam and placebo in the elderly population. METHODS: Single oral doses of zopiclone (7.5 mg), temazepam (20 mg) and placebo were administered in a randomized double-blind, completely counterbalanced cross-over design to 12 healthy elderly men and women (65.9 +/- 3.6 years, range 60-70 years). On each of the 3 study nights a sleep EEG was registered from 10 p.m. to 6.30 a.m. and cognitive performance tests were applied at 8 p.m., 2 a.m. (when subjects were awake for 30 min), 7 a.m. and 9 a.m. RESULTS: After zopiclone treatment, sleep continuity had significantly improved and sleep stage 4 was increased compared to temazepam and placebo. In addition, both active substances significantly reduced REM density. Neither active compound substantially altered psychomotor and memory performance. CONCLUSIONS: Zopiclone and temazepam can be considered as effective hypnotics in elderly subjects when administered in that dosage. The superiority of zopiclone on sleep architecture may be related to a more specific action of zopiclone at the GABA-A benzodiazepine receptor complex. The suppression of REM density by both compounds and their subtle effects on cognition may reflect a GABAergic mediated reduction of cholinergic neuro-transmission.

Aged↗