title: The NMDA receptor agonist DL-(tetrazol-5-yl)glycine is a highly potent excitotoxin.
abstract: 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.
authors.affiliation: Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN 46285.
authors.forename: D D
authors.initials: DD
authors.lastname: Schoepp
authors.forename: W H
authors.initials: WH
authors.lastname: Lunn
authors.forename: C R
authors.initials: CR
authors.lastname: Salhoff
authors.forename: J W
authors.initials: JW
authors.lastname: McDonald
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000187:drug effects* / Q000201:enzymology; D002795:Choline O-Acetyltransferase / Q000032:analysis; D005260:Female; D005968:Glutamate Decarboxylase / Q000032:analysis; D005971:Glutamates / Q000633:toxicity; D005998:Glycine / Q000031:analogs & derivatives* / Q000633:toxicity; D008297:Male; D016202:N-Methylaspartate / Q000633:toxicity; D009410:Nerve Degeneration / Q000187:drug effects*; D051381:Rats; D017207:Rats, Sprague-Dawley; D016194:Receptors, N-Methyl-D-Aspartate / Q000187:drug effects*; D013777:Tetrazoles / Q000633:toxicity*; D005680:gamma-Aminobutyric Acid / Q000032:analysis
chemical_list: D005971:Glutamates; D016194:Receptors, N-Methyl-D-Aspartate; D013777:Tetrazoles; C066302:2,4-methanoglutamate; C073649:(tetrazol-5-yl)glycine; D005680:gamma-Aminobutyric Acid; D016202:N-Methylaspartate; D002795:Choline O-Acetyltransferase; D005968:Glutamate Decarboxylase; D005998:Glycine