(R)-3,4-DCPG

Potential antipsychotic and extrapyramidal effects of (R,S)-3,4-dicarboxyphenylglycine [(R,S)-3,4-DCPG], a mixed AMPA antagonist/mGluR8 agonist.[Pubmed:15215559]

Pol J Pharmacol. 2004 May-Jun;56(3):295-304.

An involvement of glutamatergic transmission in schizophrenia has been postulated for several years. According to that view, hypofunction of NMDA receptors and a compensatory increase in glutamate release which overstimulates non-NMDA receptors contributes to psychotic symptoms. Therefore, potential antipsychotic drugs are searched for among compounds which block AMPA receptors and inhibit glutamate release. (R,S)-3,4-dicarboxyphenylglycine [(R,S)-3,4-DCPG] is a mixed antagonist of AMPA receptors and agonist of an autoreceptor, i.e. metabotropic glutamate receptor 8. The aim of the study was to look for putative antipsychotic properties of (R,S)-3,4-DCPG in the model of locomotor stimulation induced by amphetamine or phencyclidine in mice. Moreover, a risk of extrapyramidal side-effects induced by this compound was examined, as capability to induce catalepsy in the bar test and to increase the proenkephalin mRNA expression, measured autoradiographically in striatal slices by in situ hybridization. (R,S)-3,4-DCPG (80 mg/kg i.p.) decreased the amphetamine (2.5 mg/kg s.c.)-but not phencyclidine (3 mg/kg s.c.)-induced hyperactivity. That dose of (R,S)-3,4-DCPG did not decrease the spontaneous locomotor activity of mice. However, a dose of 100 mg/kg ip of that compound evoked catalepsy and enhanced the catalepsy and striatal proenkephalin mRNA expression induced by haloperidol (1-2 mg/kg i.p.). The study seems to suggest that (R,S)-3,4-DCPG may possess antipsychotic properties at doses close to those evoking extrapyramidal side-effects which speaks for its rather typical than atypical neuroleptic profile.

Anticonvulsant activity of 3,4-dicarboxyphenylglycines in DBA/2 mice.[Pubmed:11311902]

Neuropharmacology. 2001 Apr;40(5):732-5.

The 3,4-dicarboxyphenylglycines (3,4-DCPG) inhibit sound-induced seizures in DBA/2 mice with the racemate being notably more potent than either isomer (ED(50) (nmol, i.c.v.)): (RS)-3,4-DCPG (0.004; 86 mg/kg, i.p.)>>the mGlu(8) agonist (S)-3,4-DCPG (0.11)>the AMPA antagonist (R)-3,4-DCPG (0.38). A potentiation of anticonvulsant activity between AMPA and mGlu(8) receptors was confirmed by combining (R)-3,4-DCPG with the mGlu(8) agonist (RS)-4-phosphonophenylglycine. This potentiating mechanism provides a novel strategy for the treatment of epileptic seizures.

Dicarboxyphenylglycines antagonize AMPA- but not kainate-induced depolarizations in neonatal rat motoneurones.[Pubmed:9455991]

Eur J Pharmacol. 1997 Nov 5;338(2):111-6.

Ionotropic glutamate receptors have been categorized into three main groups according to the selective agonists that activate them, the N-methyl-D-aspartate (NMDA), (S)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propanoic acid (AMPA) and (2S,3S,4S)-3-carboxymethyl-4-isopropenylpyrrolidine-2-carboxylic acid (kainate) receptors. Both AMPA and kainate induce depolarizations in neonatal rat spinal motoneurones. However, selective antagonists capable of discriminating between the effects of these two antagonists are not widely available. As part of a search for such compounds we report the actions of (RS)-3,4-dicarboxyphenylglycine (DCPG) and (RS)-3,5-dicarboxyphenylglycine on agonist-induced motoneuronal depolarizations in the neonatal rat spinal cord preparation. In addition, the actions of (R)- and (S)-3,4-DCPG are also described. (RS)-3,4-DCPG and (RS)-3,5-DCPG antagonized AMPA-induced depolarizations (apparent Kd = 137 microM (n = 3) and 167 microM (n = 5), respectively). However, (RS)-3,5-DCPG (1 mM) potentiated responses due to kainate (n = 5) while (RS)-3,4-DCPG (1 mM) displayed weak antagonism of these responses (apparent Kd > 12 mM, n = 3). (RS)-3,4- and (RS)-3,5-DCPG at 500 microM both displayed antagonism at the NMDA receptor (apparent Kd = 472 microM and 346 microM, respectively) and a postsynaptic subgroup I metabotropic glutamate receptor activated by (1S,3R)-ACPD. The AMPA receptor antagonist activity of (RS)-3,4-DCPG was shown to reside in the (R)-enantiomer (apparent Kd = 77 microM, n = 3). The same isomer was responsible for the NMDA receptor antagonism while showing little or no antagonism of kainate-induced depolarizations (apparent Kd > 3 mM, n = 3), and a weak antagonistic effect at (1S,3R)-ACPD receptors. (S)-3,4-DCPG (500 microM) was unable to antagonize kainate-induced depolarizations, showed weak or no antagonism of NMDA- and AMPA-induced depolarizations, but antagonized (1S,3R)-ACPD-induced depolarizations. Thus (RS)-3,4-, (RS)-3,5- and (R)-3,4-DCPG demonstrate useful discrimination of responses due to AMPA and kainate, strongly suggesting that pharmacologically distinct AMPA and kainate receptors exist in motoneurones in the neonatal rat spinal cord.