U-90042, a sedative/hypnotic compound that interacts differentially with the GABAA receptor subtypes.
U-90042 is a structurally novel compound that has comparable affinities for binding to three recombinant subtypes of the gamma-aminobutyric acidA receptor: alpha 1 beta 2 gamma 2, alpha 3 beta 2 gamma 2 and alpha 6 beta 2 gamma 2. The relatively high affinity for the alpha 6 beta 2 gamma 2 subtype is similar to the benzodiazepine (BZ) partial inverse agonist Ro 15-4513 and different from BZ sedative/hypnotics such as diazepam and zolpidem. In the present study, U-90042 (3 mg/kg i.p.) suppressed locomotor activity and impaired rotarod performance in mice. These effects were not antagonized by flumazenil. The sedative effect was further confirmed in rats (10 mg/kg i.p.) and monkeys (1 mg/kg p.o.) by an increase of behavioral sleep and a corresponding electroencephalographic frequency spectral shift. Unlike the BZ hypnotics, U-90042 (10 mg/kg i.p.) produced no amnesia in the one-trial passive avoidance response in mice but antagonized diazepam-induced amnesia. In rats trained to discriminate an injection of diazepam from saline, U-90042 produced predominantly vehicle-appropriate responses, even at depressant doses. The in vivo diazepam-antagonist effect of U-90042 is consistent with its low intrinsic activity and diazepam-antagonism at the gamma-aminobutyric acidA alpha 1 beta 2 gamma 2 and alpha 3 beta 2 gamma 2 receptor subtypes. The receptor mechanism for the sedative/hypnotic effect is not clear at this time.
D000818:Animals; D001362:Avoidance Learning / Q000187:drug effects; D001569:Benzodiazepines / Q000037:antagonists & inhibitors*; D004193:Discrimination Learning; D000431:Ethanol / Q000008:administration & dosage; D005260:Female; D006993:Hypnotics and Sedatives / Q000378:metabolism / Q000494:pharmacology*; D008253:Macaca mulatta; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects; D010069:Oxadiazoles / Q000378:metabolism / Q000494:pharmacology*; D011810:Quinoxalines / Q000378:metabolism / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D018079:Receptors, GABA / Q000187:drug effects* / Q000378:metabolism; D011994:Recombinant Proteins; D019966:Substance-Related Disorders
D006993:Hypnotics and Sedatives; D010069:Oxadiazoles; D011810:Quinoxalines; D018079:Receptors, GABA; D011994:Recombinant Proteins; C096761:U 90042; D001569:Benzodiazepines; D000431:Ethanol