NMDA Receptor Glycine-site Agonists

Schematic model of synaptic glycine regulation by glycine transport inhibitors 

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Recent studies have identified abnormalities associated with schizophrenia that interfere with the activation of the glycine modulatory site of the NMDA receptor (Coyle and Tsai 2004). Further, the use of NMDA receptor glycine site agonists such as glycine, o-serine or o-cycloserine in clinical trials has demonstrated some efficacy in ameliorating the negative symptoms and cognitive disabihties in schizophrenics (Coyle and Tsai 2004). 

In addition to the glutamate and glycine sites on the NMDA receptor, there also exist polyamine sites which are activated by the naturally occurring polyamines spermine and spermidine. Specific divalent cation sites are also associated with the NMDA receptor, namely the voltage-dependent magnesium site and the inhibitory zinc site. In addition to the excitatory amino acids, the natural metabolite of brain tryptophan, quinolinic acid, can also act as an agonist of the NMDA receptor and may contribute to nerve cell death at high concentrations. 

D-cycloserine and (-l-R)-HA-966 are partial agonists at the glycincB site with different levels of intrinsic activity (Karcz-Kubicha et al. 1997). Although these systemically active partial agonists do not induce receptor desensitization they have favourable therapeutic profiles in some in vivo models (Lanthorn 1994 see Danysz and Parsons 1998). This may, in part, be due to their own intrinsic activity as agonists at the glycines site, which would serve to preserve a certain level of NMDA receptor function even at very high concentrations (Danysz and Parsons 1998). 

M. Jansen, G. Dannhardt (2003). Antagonists and agonists at the glycine site of the NMDA receptor for therapentic interventions. Eur. J. Med. Chem. 38 661-670. 

Laird, J. M. A., Mason, G. S., Webb, J., Hill, R. G., Hargreaves, R. J. Effects of a partial agonist and a full antagonist acting at the glycine site of the NMDA receptor on inflammation-induced mechanical hyperalgesia in rats, Br. J. Pharmacol. 1996, 117, 1487-1492. 

Millan, M. J. and Seguin, L. (+)-HA 966, a partial agonist at the glycine site coupled to NMDA receptors, blocks formalin-induced pain in mice, Eur. J. Pharmacol. 1993, 238, 445-447. 

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