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

Journal Article · Mon Jan 01 00:00:00 EST 1990 · Proceedings of the National Academy of Sciences of the United States of America; (USA)

DOI:https://doi.org/10.1073/pnas.87.1.347· OSTI ID:6829534

Singh, L; Donald, A E; Foster, A C; Hutson, P H; Iversen, L L; Iversen, S D; Kemp, J A; Leeson, P D; Marshall, G R; Oles, R J; Priestley, T; Thorn, L; Tricklebank, M D; Vass, C A; Williams, B J ^[1]

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1. Merck Sharp and Dohme Research Labs., Essex (England)

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 ({sup 3}H)glycine binding to rat cerebral cortex synaptic membranes with an IC{sub 50} of 12.5 {mu}M, whereas (-)-HA-966 had an IC{sub 50} value of 339 {mu}M. In mice, (+)-HA-966 antagonized sound and N-methyl-DL-aspartic acid (NMDLA)-induced seizures. The coadministration of D-serine dose-dependently antagonized the anticonvulsant effect of a submaximal dose of (+)-HA-966 against NMDLA-induced seizures. The sedative/ataxic effect of racemic HA-966 was mainly attributable to 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.

• OSTI ID: 6829534
• Journal Information: Proceedings of the National Academy of Sciences of the United States of America; (USA), Vol. 87:1; ISSN 0027-8424
• Country of Publication: United States
• Language: English

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
BRAIN
CROSS-LINKING
HYPNOTICS AND SEDATIVES
ENANTIOMORPHS
NEUROREGULATORS
RECEPTORS
TRITIUM COMPOUNDS
ASPARTIC ACID
BIOCHEMICAL REACTION KINETICS
DOPAMINE
GLYCINE
LIGANDS
MICE
PHYSIOLOGY
RATS
AMINES
AMINO ACIDS
ANIMALS
AROMATICS
AUTONOMIC NERVOUS SYSTEM AGENTS
BODY
CARBOXYLIC ACIDS
CARDIOTONICS
CARDIOVASCULAR AGENTS
CENTRAL NERVOUS SYSTEM
CENTRAL NERVOUS SYSTEM DEPRESSANTS
CHEMICAL REACTIONS
DRUGS
HYDROGEN COMPOUNDS
HYDROXY COMPOUNDS
KINETICS
MAMMALS
MEMBRANE PROTEINS
NERVOUS SYSTEM
ORGANIC ACIDS
ORGANIC COMPOUNDS
ORGANS
PHENOLS
POLYMERIZATION
POLYPHENOLS
PROTEINS
REACTION KINETICS
RODENTS
SYMPATHOMIMETICS
VERTEBRATES
550201* - Biochemistry- Tracer Techniques