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)-(+)-enantiomer 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 microM, whereas (-)-HA-966 had an IC50 value of 339 microM. 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 microM compared with (-)-HA-966, which has an IC50 = 708 microM. 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 pKb = 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 micrograms into the cerebral ventricles per mouse) antagonized the anticonvulsant effect of a submaximal dose of (+)-HA-966 (100 micrograms 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 greater than 25-fold more potent than the (+)-enantiomer. It is suggested that, as in the case of the sedative gamma-butyrolactone, disruption of striatal dopaminergic mechanisms may be responsible for this action.
Singh
L
L
Merck Sharp & Dohme Research Laboratories, Neuroscience Research Centre, Harlow, Essex, United Kingdom.
Donald
A E
AE
Foster
A C
AC
Hutson
P H
PH
Iversen
L L
LL
Iversen
S D
SD
Kemp
J A
JA
Leeson
P D
PD
Marshall
G R
GR
Oles
R J
RJ
D015107:4-Butyrolactone / Q000494:pharmacology*; D000161:Acoustic Stimulation; D000818:Animals; D001224:Aspartic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism / Q000502:physiology*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism; D005663:Furans / Q000494:pharmacology*; D005998:Glycine / Q000378:metabolism / Q000502:physiology*; D066298:In Vitro Techniques; D007536:Isomerism; D007700:Kinetics; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D051379:Mice; D008811:Mice, Inbred DBA; D009043:Motor Activity / Q000187:drug effects; D016202:N-Methylaspartate; D011760:Pyrrolidinones / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D018009:Receptors, Glycine; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter / Q000187:drug effects / Q000502:physiology*; D012016:Reference Values; D012640:Seizures / Q000503:physiopathology; D012701:Serotonin / Q000378:metabolism
D005663:Furans; D011760:Pyrrolidinones; D018009:Receptors, Glycine; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter; D001224:Aspartic Acid; D012701:Serotonin; D016202:N-Methylaspartate; C001369:1-hydroxy-3-amino-2-pyrrolidone; D015107:4-Butyrolactone; D005998:Glycine; D004298:Dopamine