Strychnine-insensitive

Glycine receptor function is modulated by alcohols and anesthetics [4]. Amino acid residue al(S267) is critical for alcohol potentiation, as mutation to small residues (Gly, Ala) enhance, and mutation to large residues (His, Cys, Tyr) diminish the ethanol effect. Glycine recqrtor modulation by Zn2+ involves structural determinants located within the large N-terminal domain. Additional glycinergic modulators include neuroactive steroids and the anthelmintic, ivermectin, which activates glycine receptors by a novel, strychnine-insensitive mechanism. 

Ishimaru, M, Kurumaji, A and Toru, M (1994) Increases in strychnine-insensitive glycine binding sites in cerebral cortex of chronic schizophrenics evidence for glutamate hypothesis. Biol. Psychiat. 35 84-95. 

Based on several years of experience and analyses, some exceptions have been introduced. The Na+/K+ ATPase assay is screened at 3 x 10 M because of a low hit rate. The cutoff for IC50 follow-up has been raised to 40% inhibition for CCKb, GABAa, GABAB(ib), Kainate, Glycine (strychnine-insensitive), N (neuronal alpha bungarotoxin insensitive) and PAF assays. 

While its mechanism of action has not been clearly established, felbamate shows some activity as an inhibitor of voltage-dependent sodium channels in a manner similar to that of phenytoin and carbamazepine. Felbamate also interacts at the strychnine-insensitive glycine recognition site on the NMDA receptor-ionophore complex. Whether this effect is important to its anticonvulsant activity is not clear. 

In medicinal chemistry, the strychnine-insensitive receptor has received more attention. For example, the 5-nitro derivative of 6,7-dichloroquinoxalinedione has been identified as a highly potent antagonist of the glycine snbsite on the NMDA receptor. 

Danysz, W., Fadda, E., Wroblewski, J. T., Costa, E. [3H]D-Serine labels strychnine-insensitive glycine recognition sites of rat central nervous system, Life Sci. 1990, 46, 155-164. 

Novel indole-2-carboxylates as ligands for the strychnine-insensitive N-methyl-D-aspartate-linked glycine receptor, J. Med. Chem. 1991, 34, 1283-1292. 

CGP68730A a N-methyl-D-aspartate antagonist acting at the strychnine-insensitive glycine site, Prog. Neuropsychopharmacol. Biol. Psychiatry 2000, 24, 547-670. 

Figure 14.8. Sites of action of endogenous ligands and drugs that modulate the action of excitatory amino acids on the NMDA receptor. Recent evidence shows that glutamate (Glut) and possibly other excitatory amino acids released from presynaptic terminals activate the NMDA receptor site on postsynaptic membranes, resulting in the opening of the Na+/Ca++ channels. Glycine acts on a strychnine-insensitive receptor while polyamines (e.g. spermine and spermidine) also have a modulatory role. Conversely Zn++ and Mg++ and drugs like phencyclidine (PCP) block the ion channel by acting at various sites on the NMDA receptor complex or...

NMDA-Glu-Rs are 4 to 5 subunit complexes of NR1, NR2 (A-D) and NR3 subunits with sites for various modulatory ligands including NMDA, Gly (at a strychnine-insensitive site) and ion channel blocking entities such as polyamines, Zn2+ and Mg2+ (Table 3.3). 

Chiorokynuremc acid] (quinoline) Synthetic Strychnine-insensitive Gly-R (NMDA-Glu-R) antagonist... 

Strychnine-sensitive Gly-R agonist (Strychnine-insensitive NMDA Glu-R co-agonist)... 

Pullan. L.M. era/. (1992) Comparison of binding at strychnine-sensitive (inhibitory glycine receptor) and strychnine-insensitive (JV-methyl-D-aspartate receptor) glycine binding sites. Neurosd. Lett. 148. 199-201,... 

Figure 6.8. Possible sites of interaction of antiepileptic drugs on glutamate-mediatedtransmission (after Ref 174). The NMDA receptor is associated with an ion channel permeable to Na" and and is associated with a number of modulatory sites, including a strychnine-insensitive glycinebinding site. Glycine is an absolute requirement for the receptor-channel complex to enter the open state.

Affinity of benzoazepine derivatives for the strychnine-insensitive binding site... 

Chiamulera, C., Costa, S., Reggiani, A., 1990. Effect of NMDA and strychnine-insensitive glycine site antagonists on NMDA-mediated convulsions and learning. Psychopharmacology 102, 551. 

Di Fabio, R., Gaviraghi, G., Reggiani, A., 1996. Strychnine-insensitive glycine binding site and the NMDA receptor. La Chimica e ITndustria 78, 283-289. 

The NMDA receptor for glutamate has a number of modulatory sites that affect its activity (i.e. regulating the influx of cations (mainly Ca +) via a cation channel located adjunct to the receptor). Within the channel, there is a binding site for dissociative anesthetics such as phencyclidine (PCP) and ketamine, which serve as non-competitive antagonists. There is also a strychnine-insensitive binding site for the co-agonist glycine. 

Regulatory sites Benzodiazepine (central) Benzodiazepine (peripheral) Glycine (strychnine insensitive) Glycine (strychnine sensitive) Phencyclidine MK801 Sigma... 

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