ENANTIOMERS OF HA-966 (3-AMINO-1-HYDROXYPYRROLID-2-ONE) EXHIBIT DISTINCT CENTRAL NERVOUS-SYSTEM EFFECTS - (+)-HA-966 IS A SELECTIVE GLYCINE N-METHYL-D-ASPARTATE RECEPTOR ANTAGONIST, BUT (-)-HA-966 IS A POTENT GAMMA-BUTYROLACTONE-LIKE SEDATIVE

The antagonist effect of (±)-3-amino-1-hydroxypyrrolid-2-one (HA-966) at the N-methyl-D-aspartate (NMDA) receptor occurs through a selective interaction with the glycine modulatory site within the receptor complex. When the enantiomers of (±)-HA-966 were resolved, the (R)-(+)-enantiomr was found to be a selective glycine/NMDA receptor antagonist, a property that accounts for its anticonvulsant activity in vivo. In contrast, the (S)-(-)-enantiomer was only weakly active as an NMDA-receptor antagonist, but nevertheless it possessed a marked sedative and muscle relaxant action in vivo. In radioligand binding experiments, (+)-HA-966 inhibited strychnine-insensitive [3H]glycine binding to rat cerebral cortex synaptic membranes with an IC50 of 12.5 μM, whereas (-)-HA-966 had an IC50 value of 339 μM. In electrophysiological experiments, (+)-HA-966 selectively antagonized NMDA receptor responses in rat cortical slices, whereas the (-)-enantiomer was much weaker. On cultured cortical neurones (+)-HA-966 inhibited glycine-potentiated NMDA responses with an IC50 = 13 μM compared with (-)-HA-966, which has an IC50 = 708 μM. In agreement with findings with racemic HA-966, even high concentrations of (+)-HA-966 did not completely inhibit NMDA responses, suggesting that (+)-HA-966 is a low-efficacy partial agonist. (+)-HA-966 produced parallel shifts to the right of the glycine concentration curve for potentiation of NMDA responses, resulting in an estimated pK(b) = 5.6. In mice, (+)-HA-966 antagonized sound and N-methyl-DL-aspartic acid (NMDLA)-induced seizures with ED50 values of 52.6 mg/kg of body weight (i.p.) and 900 mg/kg (i.v.), respectively. The coadministration of D-serine dose-dependently (10-100 μg into the cerebral ventricles per mouse) antagonized the anticonvulsant effect of a submaximal dose of (+)-HA-966 (100 μg administered directly into the cerebral ventricles) against NMDLA-induced seizures. The sedative/ataxic effect of racemic HA-966 was mainly attributable to the (-)-enantiomer, which was > 25-fold more potent than the (+)-enantiomer. It is suggested that, as in the case of the sedative γ-butyrolactone, disruption of striatal dopaminergic mechanisms may be responsible for this action.