D,L-(Tetrazol-5-yl) glycine: a novel and highly potent NMDA receptor agonist

Abstract

This paper describes the pharmacological activity of D,L-(tetrazol-5-yl)glycine, a structurally novel and highly potent agonist at the N-methyl-D-aspartate (NMDA) subtype of excitatory amino acid receptor. D,L-(Tetrazol-5-yl)glycine potently displaced NMDA receptor binding to rat brain membranes as measured using [ 3H]CGS19755 (IC 50 = 98 ± 7 nM) and [ 3H]glutamate (IC 50 = 36 ± 18 nM) as ligands. D,L-(Tetrazol-5-yl)glycine did not appreciably inhibit the binding of D.L-α-[5-methyl- 3H] amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), [ 3H]kainate, or [ 3H]glycine (IC 50s > 30000 nM). D,L-(Tetrazol-5-yl) glycine was more potent than NMDA or cis-methanoglutamate as a depolarizing agent in the rat cortical slice, and unlike these other agents induced rapid receptor-mediated neurotoxicity. Depolarization by D,L-(tetrazol-5-yl)glycine was antagonized by LY233053, a selective NMDA receptor antagonist. D,L-(Tetrazol-5-yl)glycine was a highly potent convulsant when given to neonatal rats (ED 50 = 0.071 mg/kg i.p.) Convulsions in neonatal rats or lethality in mice induced by D,L-(tetrazol-5-yl)glycine were selectively antagonized by competitive and non-competitive NMDA receptor antagonists. D,L-(Tetrazol-5-yl)glycine is a structurally novel (tetrazole-substituted) compound that is a highly potent and selective NMDA receptor agonist. D,L-(Tetrazol-5-yl) glycine could be used to probe further NMDA receptor function in vitro and in vivo.