title: Binding and neuropharmacological profile of zaleplon, a novel nonbenzodiazepine sedative/hypnotic.
abstract: 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.
authors.affiliation: Medical Research Laboratories, Wyeth Lederle (Japan), Ltd., 1-6-34 Kashiwa-cho, Shiki, Saitama 353, Japan. NoguchH@labs.wyeth.com
authors.forename: Hideaki
authors.initials: H
authors.lastname: Noguchi
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Kitazumi
authors.forename: Megumi
authors.initials: M
authors.lastname: Mori
authors.forename: Toshiharu
authors.initials: T
authors.lastname: Shiba
mesh_terms: D000081:Acetamides / Q000378:metabolism / Q000494:pharmacology*; D000818:Animals; D001570:Benzodiazepinones / Q000378:metabolism; D004569:Electroencephalography / Q000187:drug effects; D005445:Flunitrazepam / Q000378:metabolism; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D008297:Male; D009118:Muscimol / Q000378:metabolism; D011743:Pyrimidines / Q000378:metabolism / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D012890:Sleep / Q000502:physiology; D005680:gamma-Aminobutyric Acid / Q000494:pharmacology
chemical_list: D000081:Acetamides; D001570:Benzodiazepinones; D006993:Hypnotics and Sedatives; D011743:Pyrimidines; D009118:Muscimol; C028513:4'-chlorodiazepam; D005680:gamma-Aminobutyric Acid; D005445:Flunitrazepam; C085665:zaleplon