Denise Mary Flanagan

Stereoselective R-(+) enantiomer of HA-966 displays anxiolytic effects in rodents

Anxiolytic agents disinhibit suppressed behaviors in rodents in preclinical models of anxiety such as the non-conditioned social interaction and elevated plus maze assays and the conditioned conflict Cook and Davidson procedure. The (+) and (-) enantiomers of (+/-)-3-amino-1-hydroxy-2-pyrrolidinone (HA-966) have been resolved and revealed that R-(+)-HA-966 significantly disinhibits both non-conditioned and conditioned suppressed behavior similar to the benzodiazepine diazepam, while the S-(-) enantiomer was devoid of anxiolytic activity and only produced behavioral sedation. Furthermore, R-(+)-HA-966 lacked side-effects in rodents commonly associated with the administration of benzodiazepines such as motor incoordination and ataxia, significant interactions with ethanol, and amnesia. These data suggest that R-(+)-HA-966, an antagonist at the strychnine-insensitive glycine/NMDA receptor site, was anxioselective and lacked some of the side-effects associated with benzodiazepine anxiolytics.