Electroencephalographic properties of zaleplon, a non-benzodiazepine sedative/hypnotic, in rats.

The encephalographic (EEG) properties of zaleplon were investigated in comparison with those of other sedative hypnotics in conscious rats with chronically implanted electrodes. The oral administration of zaleplon (0.25-1.0 mg/kg), triazolam (0.0625-0.25 mg/kg), zopiclone (1.0-4.0 mg/kg), brotizolam (0.0625-0.25 mg/kg), and nitrazepam (0.125-0.5 mg/kg) lengthened the total sleep in a dose-dependent manner. On distribution of sleep-wakefulness stages, zaleplon, in particular, increased the slow wave deep sleep (SWDS), whereas triazolam, brotizolam, and nitrazepam increased the slow wave light sleep (SWLS) in a dose-dependent manner. Zopiclone significantly increased the SWDS at a dose of 2 mg/kg and both the SWLS and the SWDS at a dose of 4 mg/kg. All tested hypnotics caused no influence on fast wave sleep (FWS) at doses tested. The appearance of the sleep-inducing activity of zaleplon was more rapid than those of any compounds tested, and zaleplon significantly increased the relative EEG power density in the delta frequency band over that of triazolam at 20 and 30 min after the administration in the spectral analysis. Therefore, the present findings suggest that the non-benzodiazepine zaleplon can be expected to exhibit high practical potential as a hypnotic and is characterized by an increase in SWDS with rapid onset of hypnotic action.

Effect of zaleplon, a non-benzodiazepine hypnotic, on melatonin secretion in rabbits.

Melatonin, a major hormone secreted by the pineal gland, is known to play an important role in regulation of the circadian rhythm. (N-[3-(3-cyanopyrazolo[1,5-a]pyrimidin-7-yl)phenyl]-N-ethylacetamide (zaleplon) is a non-benzodiazepine hypnotic that acts via the benzodiazepine site of the GABA(A) receptor. In the present study, we investigated the effect of zaleplon on melatonin secretion in rabbits using RIA and compared the effect to triazolam and zopiclone. Zaleplon increased a dose-dependent concentration of melatonin in rabbit plasma collected at 30 min after intravenous administration at doses of 1 and 2 mg/kg. The zaleplon-induced increase in plasma melatonin level was not blocked by flumazenil, a benzodiazepine-receptor antagonist. In contrast, triazolam and zopiclone failed to affect the plasma melatonin level. We also investigated the effect of zaleplon on intracellular cAMP in rat pinealocytes. Consequently, zaleplon had no effect on the intracellular cAMP levels in rat pinealocytes. These results of the present studies suggest that zaleplon may promote melatonin secretion and the elevation of plasma levels of melatonin may suggest an influence of zaleplon on chronobiology.

Effect of zaleplon on learning and memory in rats.

Although structurally not a benzodiazepine, 3'-(3-cyanopyrazolo [1,5-a] pyrimidin-7-yl)- N-ethylacetamide (zaleplon) it acts via the benzodiazepine site of the GABA(A) receptor. In the present study, we investigated the effects of zaleplon on learning and memory in rats in comparison with triazolam and nitrazepam. Oral administration of zaleplon and the reference drugs dose-dependently lessened the step-through latency in the test session of a passive avoidance task and increased the latency for reaching the hidden platform in the Morris water maze task, indicating the amnesic effect of the test drugs. The amnesic liability ratio for zaleplon in the passive avoidance task to sleep inducing activity was 19.6, for triazolam and nitrazepam 4.2 and 5.9, respectively. The liability ratios derived from the Morris water maze task for zaleplon, triazolam and nitrazepam were 10.2, 0.9 and 0.6, respectively. The results may indicate that zaleplon has a preferential sedative effect and that the sedative dose does not interfere with learning and memory. In a binding study, zaleplon displaced bound [(3)H]flunitrazepam from membrane preparations from the rat hippocampus with an IC(50) of 4,454.5 nM. In contrast, triazolam and nitrazepam displaced the binding of [(3)H]flunitrazepam to the membrane with IC(50) values of 15.5 nM and 83.6 nM, respectively. The efficacy of zaleplon for the competitive inhibition of [(3)H]flunitrazepam binding to the membrane preparation from hippocampus was thus less than that of triazolam and nitrazepam. These results suggest that zaleplon is characterized by a reduced amnesic liability, which may be due to its low affinity for the benzodiazepine site of the GABA(A) receptor in the hippocampus.

Binding and neuropharmacological profile of zaleplon, a novel nonbenzodiazepine sedative/hypnotic.

The binding properties of CL284,846 (zaleplon), a novel nonbenzodiazepine sedative/hypnotic, at benzodiazepine receptor subtypes were evaluated. Zaleplon was 14.3 times more potent at inhibiting [3H]flunitrazepam binding to membrane preparations of the cerebellum than to membrane preparations of the spinal cord. The gamma-aminobutyric acid (GABA) ratio of zaleplon was 2.07. Zaleplon produced significant increases in muscimol binding similar to those of diazepam, and it was antagonized by flumazenil. Furthermore, zaleplon showed little affinity for other receptors. Spectral analysis of the electroencephalogram (EEG) of rabbits showed that zaleplon and 3-methyl-6-[3-(trifluoromethyl) phenyl]-1,2,4,-triazolo [4,3-beta] pyridazine (CL218,872), an omega(1) receptor-selective compound (1 mg/kg, i.v., respectively), produced large increases in energy of the delta frequency band without affecting the energy of the alpha and beta frequency bands. In contrast, intravenous administration of triazolam and zopiclone increased the energy of the beta frequency band at doses of 0.1 and 2 mg/kg, respectively. In addition, the zaleplon-induced increase in the energy of the delta frequency band was antagonized by pretreatment with flumazenil (1 mg/kg, i.v.), which did not affect the spontaneous EEG alone. The present results clearly demonstrate that zaleplon is a selective full agonist of the omega(1) receptor subtype, and thus, zaleplon may induce responses closely resembling the physiological pattern of slow wave sleep.