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 04:00:00 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), Journal Name: Proceedings of the National Academy of Sciences of the United States of America; (USA) Vol. 87:1; ISSN 0027-8424; ISSN PNASA
• Country of Publication: United States
• Language: English

Related Subjects

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