Abstract |
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.
|
Authors | A H Tang, M W Smith, D B Carter, W B Im, P F VonVoigtlander |
Journal | The Journal of pharmacology and experimental therapeutics
(J Pharmacol Exp Ther)
Vol. 275
Issue 2
Pg. 761-7
(Nov 1995)
ISSN: 0022-3565 [Print] United States |
PMID | 7473164
(Publication Type: Journal Article)
|
Chemical References |
- Hypnotics and Sedatives
- Oxadiazoles
- Quinoxalines
- Receptors, GABA
- Recombinant Proteins
- U 90042
- Benzodiazepines
- Ethanol
|
Topics |
- Animals
- Avoidance Learning
(drug effects)
- Benzodiazepines
(antagonists & inhibitors)
- Discrimination Learning
- Ethanol
(administration & dosage)
- Female
- Hypnotics and Sedatives
(metabolism, pharmacology)
- Macaca mulatta
- Male
- Mice
- Motor Activity
(drug effects)
- Oxadiazoles
(metabolism, pharmacology)
- Quinoxalines
(metabolism, pharmacology)
- Rats
- Rats, Inbred F344
- Receptors, GABA
(drug effects, metabolism)
- Recombinant Proteins
- Substance-Related Disorders
|