Different stereoselectivity of the enantiomers of HA-966 (3-amino-1-hydroxy-2-pyrrolidinone) for neuroprotective and anticonvulsant actions in vivo

  title={Different stereoselectivity of the enantiomers of HA-966 (3-amino-1-hydroxy-2-pyrrolidinone) for neuroprotective and anticonvulsant actions in vivo},
  author={Mark G. Vartanian and Charles Price Taylor},
  journal={Neuroscience Letters},
Anticonvulsant effects of the glycine/NMDA receptor ligands d‐cycloserine and d‐serine but not R‐(+)‐HA‐966 in amygdala‐kindled rats
Pharmacological intervention at the strychnine‐insensitive glycine receptor by high‐efficacy partial agonists with systemic bioavailability may be an effective means of increasing seizure threshold without concomitantly inducing PCP‐like adverse effects.
Neuroprotective effects of kynurenine-3-hydroxylase inhibitors in models of brain ischemia.
It is demonstrated that ischemic neuronal damage may be significantly decreased by inhibiting kynurenine hydroxylase.
Anxiolytic effect of glycine antagonists microinjected into the dorsal periaqueductal grey
Results indicate that microinjections of 7-Cl-KY and HA-966 into the DPAG cause anxiolytic effects in two different models of anxiety and support the proposal that NMDA-mediated neurotransmission in theDPAG may be related to anxiety and panic.
Localization of an Anatomic Substrate for the Anticonvulsant Activity Induced by D‐Cycloserine
Results indicate that D‐cycloserine acts through the strychnine‐insensitive glycine site to inhibit the tonic hindlimb extension component of maximal electroshock seizures (MES), and indicate that the anticonvulsant activity of D‐ cycloserine is mediated by RPO.
Comparison of the Neurochemical and Behavioral Effects Resulting from the Inhibition of Kynurenine Hydroxylase and/or Kynureninase
The results of the present experiments indicate the possibility of increasing the neosynthesis of kynurenic acid by inhibiting the enzymes that metabolize kynurenine to 3‐hydroxykynureninase or to anthranilic acid.


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.
  • L. Singh, A. E. Donald, R. Oles
  • Biology, Chemistry
    Proceedings of the National Academy of Sciences of the United States of America
  • 1990
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.
HA-966 antagonizes N-methyl-D-aspartate receptors through a selective interaction with the glycine modulatory site
  • A. Foster, J. Kemp
  • Biology
    The Journal of neuroscience : the official journal of the Society for Neuroscience
  • 1989
Previous experiments with HA-966 may now be interpreted to suggest that activation of the glycine site on the NMDA receptor occurs in vivo and is important for the participation of NMDA receptors in synaptic transmission.
Pharmacology of Cl‐966: A potent GABA uptake inhibitor, in vitro and in experimental animals
In mice, rats, dogs, and monkeys, Cl‐966 interferes with normal behavior, causing ataxia, reduced responsivenes and myoclonus, and may be explained by its inhibitory effect on GABA uptake.
Stereoselectivity for the (R)‐Enantiomer of HA‐966 (l‐Hydroxy‐3‐Aminopyrrolidone‐2) at the Glycine Site of the N‐Methyl‐d‐Aspartate Receptor Complex
The stereoselectivity of the glycine antagonist site of the N‐methyl‐d‐aspartate receptor complex is demonstrated in a variety of tissues and assays and confirms the specificity of N‐ methyl‐ d‐as partate receptors in glutamate‐evoked contractions of the guinea pig ileum, and supports their similarity to central N‐ethyl‐d-aspartates receptors.