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. The relatively short duration of action of LY233053 may make this compound particularly advantageous as a
neuroprotective agent in the treatment of acute conditions such as
cerebral ischemia.