William Henry Walker Lunn

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

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 (IC50 = 98 +/- 7 nM) and [3H]glutamate (IC50 = 36 +/- 18 nM) as ligands. D,L-(Tetrazol-5-yl)glycine did not appreciably inhibit the binding of D,L-alpha-[5-methyl-3H] amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA), [3H]kainate, or [3H]glycine (IC50s greater than 30,000 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 (ED50 = 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.

Heteroatom-substitution as a strategy for increasing the potency of competitive NMDA antagonists

We report the synthesis and characterization of compounds that are competitive NMDA receptor antagonists. Significant increases in affinity and potency were obtained by incorporation of a heteroatom into the substructure of the tetrazole-substituted amino acid LY233053.

The NMDA receptor agonist DL-(tetrazol-5-yl) glycine is a highly potent excitotoxin

DL-(Tetrazol-5-yl)glycine is a highly selective N-methyl-D-aspartate (NMDA) receptor agonist with nanomolar in vitro potency. Previous work showed that DL-(tetrazol-5-yl)glycine has greater affinity and efficacy at NMDA receptors than other NMDA receptor agonists such as cis-methanoglutamate and NMDA. In this study, the in vivo excitotoxic potency of DL-(tetrazol-5-yl)glycine was compared to cis-methanoglutamate and NMDA. Adult (250-300 g) and neonatal (7-day-old) rats were anesthetized and compounds were unilaterally injected into the striatum. In adult rats DL-(tetrazol-5-yl)glycine (0.3-1.0 nmol/microliters) produced highly significant losses of striatal gamma-aminobutyric acid neurons (as indexed by glutamic acid decarboxylase activity) and cholinergic neurons (as indexed by choline acetyltransferase activity). Dose-response showed that DL-(tetrazol-5-yl)glycine was about 100 and 500 times more potent than cis-methanoglutamate and NMDA, respectively. In neonatal rats, DL-(tetrazol-5-yl)glycine (0.1-0.3 nmol/microliters) produced significant brain damage as indicated by brain weight losses 5 days later. DL-(Tetrazol-5-yl)glycine was about 50 and 150 times more potent than cis-methanoglutamate and NMDA, respectively, in the neonate. The excitotoxic potency of DL-(tetrazol-5-yl)glycine is likely due to its greater efficacy and potency at the NMDA receptor, when compared to other NMDA receptor agonists. The remarkable in vivo potency of DL-(tetrazol-5-yl)glycine in producing excitotoxic lesions makes it a useful agent to further probe NMDA receptor mediated excitotoxicity in brain pathologies.