HA-966 acts at a modulatory glycine site to inhibit N-methyl-D-aspartate-evoked neurotransmitter release.
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.
Keith
R A
RA
Department of Pharmacology, ICI Americas Inc., Wilmington, DE 19897.
Mangano
T J
TJ
Meiners
B A
BA
Stumpo
R J
RJ
Klika
A B
AB
Patel
J
J
Salama
A I
AI
D000818:Animals; D001224:Aspartic Acid / Q000037:antagonists & inhibitors; D001665:Binding Sites / Q000187:drug effects; D003986:Dibenzocycloheptenes / Q000494:pharmacology; D016291:Dizocilpine Maleate; D005998:Glycine / Q000494:pharmacology / Q000502:physiology*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D016202:N-Methylaspartate; D018377:Neurotransmitter Agents / Q000378:metabolism*; D009638:Norepinephrine / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology*; D051381:Rats; D013331:Strychnine / Q000494:pharmacology
D003986:Dibenzocycloheptenes; D018377:Neurotransmitter Agents; D010879:Piperazines; D011760:Pyrrolidinones; D001224:Aspartic Acid; D016202:N-Methylaspartate; D016291:Dizocilpine Maleate; C001369:1-hydroxy-3-amino-2-pyrrolidone; D013331:Strychnine; C015068:1-(3-chlorophenyl)piperazine; D005998:Glycine; D009638:Norepinephrine