DL-Tetrazol-5-ylglycine, a highly potent NMDA agonist: its synthesis and NMDA receptor efficacy

Abstract

At physiological pH, the spatial arrangement of the three charges of DL-tetrazol-5-ylglycine (5) could be viewed as similar to those found in certain conformations of the two excitatory amino acids (EAAs)--aspartic and glutamic acids. Given significant binding to one or more EAA receptors, 5 would offer unique modeling and perhaps biological opportunities. We have previously shown it to be the most potent NMDA agonist known, with a unique and marked in vitro neutrotoxicity at depolarizing concentrations. Now we report the details required for its synthesis, together with its potency and efficacy in two assays of functional activation of the NMDA receptor, namely agonist-influenced [3H]MK801 binding and agonist-induced release of the neurotransmitter [3H]-norepinephrine from brain slices. In both these assays DL-tetrazol-5-ylglycine proved to be more potent and efficacious than NMDA and cis-methanoglutamate. It was more potent than, and equally efficacious to, L-glutamate in [3H]MK801 binding. The structural features of 5 may well reflect optimal agonist interaction at the NMDA receptor site. (We considered the possibility that some decarboxylation of DL-tetrazol-5-ylglycine may have occurred during testing. This would give 5-(aminomethyl)tetrazole (13), the tetrazole acid analog of glycine; and glycine is involved in NMDA receptor activation. Compound 13 does not affect [3H]glycine binding at the strychnine-insensitive glycine binding site, and [3H]MK801 binding studies showed that the (aminomethyl)-tetrazole, even if is formed, would probably have no effect on the activity of tetrazol-5-ylglycine at the NMDA receptor.

An efficient synthesis, X-ray and spectral characterization of biphenyl derivatives

“…19,20 In the present work reaction of compound 7 with sodium azide in presence of triethylamine hydrochloride gave the final compound 9 in fairly low yield (48%) and also time required for the reaction was 52 h. Therefore, we designed a facile new scheme with improvement in the yield (scheme 2).…”

“…150-151 • C). (13): 1 H NMR (300 MHz, DMSO-d 6 )δ 4.48 (s, 2H, CH 2 ), 7.00-7.84 (m, 23H, ArH); 13 C NMR (300 MHz,64.6,111.9,127.4,127.9,128.2,128.4,129.0,129.2,129.4,129.5,127.4,135.1,135.4,136,136.8,141.0,144.0,151.4 (21), 271 (28), 246 (12), 244 (19), 153 (100), 77 (67); Anal. Calcd.…”

N-(Cyanomethyl)benzamide

“…Data collection: APEX2 (Bruker, 2005); cell refinement: SAINT (Bruker, 2005); data reduction: SAINT; program(s) used to solve structure: SHELXS97 (Sheldrick, 2008); program(s) used to refine structure: SHELXL97 (Sheldrick, 2008); molecular graphics: PLATON (Spek, 2009) and ORTEP-3 for Windows (Farrugia, 1997); software used to prepare material for publication: publCIF (Westrip, 2010). Tetrazoles derivatives are an important class of compounds, which can be used in the fields of bioorganic and medicinal chemistry as antibacterials, anti-cancer, heart disease, neurodegenerative disease, and antifungal activity (Smissman et al,1976;McGuire et al, 1990;Lunn et al, 1992;Itoh et al, 1995;Upadhayaya et al, 2004;Wu et al, 2008;Rostom et al, 2009. The tetrazole moiety has long been established as a bioisostere of a carboxyl unit (Burger, 1991). A major advantage of tetrazoles over carboxylic acids is that they are resistant to many biological metabolic degradation pathways (Singh et al, 1980).…”

“…For the biological activity and medicinal properties of tetrazole derivatives, see : Smissman et al (1976); McGuire et al (1990); Lunn et al (1992); Itoh et al (1995); Upadhayaya et al (2004); Wu et al (2008); Rostom et al (2009);Burger (1991); Singh et al (1980). For the synthetic procedure, see: Adams & Langley (1941a,b).…”

Seizure responses and induction of Fos by the NMDA Agonist (tetrazol-5-yl)glycine in a genetic model of NMDA receptor hypofunction

“…However, TZG can induce tonic-clonic seizures and exhibits a very steep dose response for seizure induction (Schoepp et al, 1991;Lunn et al, 1992). Consitent with the study of Inada et al (2007), Schoepp et al (1991) found that a TZG dose of 0.75 mg/kg did not induce seizures in any mice tested.…”