HA-966 acts at a modulatory glycine site to inhibit N-methyl-D-aspartate-evoked neurotransmitter release

Eur J Pharmacol. 1989 Aug 3;166(3):393-400. doi: 10.1016/0014-2999(89)90351-8.

Abstract

The role of endogenous glycine in supporting N-methyl-D-aspartate (NMDA)-evoked neurotransmitter release was investigated. HA-966 (1-hydroxy-3-aminopyrrolidone-2) inhibited NMDA-evoked release of [3H]norepinephrine from rat hippocampal brain slices, but was much less effective in inhibiting [3H]norepinephrine release evoked by kainic acid (KA). Glycine (1 mM) reversed the HA-966 (1 mM) antagonism of NMDA-evoked release of [3H]norepinephrine. Strychnine (10 microM) had no effect on the ability of glycine to reverse HA-966 antagonism of NMDA-evoked neurotransmitter release. Other amino acids were also capable of reversing the HA-966 antagonism of NMDA-evoked [3H]norepinephrine release with a rank order of potency: D-serine greater than or equal to glycine much greater than L-serine approximately beta-alanine. These same compounds inhibited strychnine-insensitive [3H]glycine binding to rat cortical membrane fragments with a rank order of potency: glycine greater than D-serine much greater than L-serine greater than or equal to beta-alanine. In addition, HA-966 inhibited [3H]glycine binding (IC50 = 8.5 microM). The results suggest that HA-966 antagonism of NMDA-evoked neurotransmitter release is due to the inhibition of endogenous glycine acting at a strychnine-insensitive modulatory glycine site associated with the NMDA receptor/ionophore complex.

MeSH terms

  • Animals
  • Aspartic Acid / antagonists & inhibitors
  • Binding Sites / drug effects
  • Dibenzocycloheptenes / pharmacology
  • Dizocilpine Maleate
  • Glycine / pharmacology
  • Glycine / physiology*
  • Hippocampus / drug effects
  • Hippocampus / metabolism
  • In Vitro Techniques
  • Male
  • N-Methylaspartate
  • Neurotransmitter Agents / metabolism*
  • Norepinephrine / metabolism
  • Piperazines / pharmacology
  • Pyrrolidinones / pharmacology*
  • Rats
  • Strychnine / pharmacology

Substances

  • Dibenzocycloheptenes
  • Neurotransmitter Agents
  • Piperazines
  • Pyrrolidinones
  • Aspartic Acid
  • N-Methylaspartate
  • Dizocilpine Maleate
  • 1-hydroxy-3-amino-2-pyrrolidone
  • Strychnine
  • 1-(3-chlorophenyl)piperazine
  • Glycine
  • Norepinephrine