Pharmacological characterization of LY233053: A structurally novel tetrazole-substituted competitive N-methyl-D-aspartic acid antagonist with a short duration of action

Journal Article · Sat Dec 01 00:00:00 EST 1990 · Journal of Pharmacology and Experimental Therapeutics; (USA)

OSTI ID:6214985

Schoepp, D D; Ornstein, P L; Leander, J D; Lodge, D; Salhoff, C R; Zeman, S; Zimmerman, D M ^[1]

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1. Eli Lilly and Company, Indianapolis, IN (USA)

This study reports the activity of a structurally novel excitatory amino acid receptor antagonist, LY233053 (cis-(+-)-4-((2H-tetrazol-5-yl)methyl)piperidine-2-carboxylic acid), the first tetrazole-containing competitive N-methyl-D-aspartic acid (NMDA) antagonist. LY233053 potently inhibited NMDA receptor binding to rat brain membranes as shown by the in vitro displacement of (3H) CGS19755 (IC50 = 107 +/- 7 nM). No appreciable affinity in (3H)alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) or (3H)kainate binding assays was observed (IC50 values greater than 10,000 nM). In vitro NMDA receptor antagonist activity was further demonstrated by selective inhibition of NMDA-induced depolarization in cortical wedges (IC50 = 4.2 +/- 0.4 microM vs. 40 microM NMDA). LY233053 was effective after in vivo systemic administration in a number of animal models. In neonatal rats, LY233053 selectively blocked NMDA-induced convulsions (ED50 = 14.5 mg/kg i.p.) with a relatively short duration of action (2-4 hr). In pigeons, LY233053 potently antagonized (ED50 = 1.3 mg/kg i.m.) the behavioral suppressant effects of 10 mg/kg of NMDA. However, a dose of 160 mg/kg, i.m., was required to produce phencyclidine-like catalepsy in pigeons. In mice, LY233053 protected against maximal electroshock-induced seizures at lower doses (ED50 = 19.9 mg/kg i.p.) than those that impaired horizontal screen performance (ED50 = 40.9 mg/kg i.p.). Cholinergic and GABAergic neuronal degenerations after striatal infusion of NMDA were prevented by single or multiple i.p. doses of LY233053. In summary, the antagonist activity of LY233053 after systemic administration demonstrates potential therapeutic value in conditions of neuronal cell loss due to NMDA receptor excitotoxicity.

• OSTI ID: 6214985
• Journal Information: Journal of Pharmacology and Experimental Therapeutics; (USA), Vol. 255:3; ISSN 0022-3565
• Country of Publication: United States
• Language: English

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
CARBOXYLIC ACIDS
CHEMICAL COMPOSITION
ASPARTIC ACID
BIOCHEMICAL REACTION KINETICS
BIOLOGICAL MODELS
BRAIN
CELL MEMBRANES
DOSE-RESPONSE RELATIONSHIPS
INHIBITION
MICE
NERVE CELLS
PIGEONS
RATS
RECEPTORS
TRACER TECHNIQUES
TRITIUM COMPOUNDS
AMINO ACIDS
ANIMAL CELLS
ANIMALS
BIRDS
BODY
CELL CONSTITUENTS
CENTRAL NERVOUS SYSTEM
HYDROGEN COMPOUNDS
ISOTOPE APPLICATIONS
KINETICS
MAMMALS
MEMBRANE PROTEINS
MEMBRANES
NERVOUS SYSTEM
ORGANIC ACIDS
ORGANIC COMPOUNDS
ORGANS
PROTEINS
REACTION KINETICS
RODENTS
SOMATIC CELLS
VERTEBRATES
550201* - Biochemistry- Tracer Techniques