(RS)-3,4-DCPG

Effects of (RS)-3,4-DCPG, a mixed AMPA antagonist/mGluR8 agonist, on aggressive behavior in mice.[Pubmed:23034312]

Rev Psiquiatr Salud Ment. 2009 Jul;2(3):133-7.

INTRODUCTION: Ionotropic and metabotropic (mGlu) receptors of glutamate have been suggested to be involved in the modulation of aggression. Thus, recent studies found reduced aggression in AMPA-type glutamate receptor GluR-A subunit-deficient mice. Likewise, mGlu1 and 5 receptors have also been implicated in aggression regulation. (RS)-3,4-DCPG is a mixed antagonist of AMPA receptors and an agonist of mGluR8. The AMPA antagonist activity of this compound is determined by its R isomer while the S isomer is responsible for its mGluR8 agonistic properties. METHODS: We analyzed the effects of (RS)-3,4-DCPG (5, 10 and 20mg/kg, ip) on agonistic encounters between male mice. Individually housed mice were exposed to anosmic opponents 30 min after drug administration. Ten min of dyadic interactions were staged between a singly housed and an anosmic mouse in a neutral area. The encounters were videotaped and the accumulated time allocated by subjects to 10 broad behavioral categories was estimated using an ethologically based analysis. RESULTS AND CONCLUSIONS: The results indicated that (RS)-3,4-DCPG produced no significant behavioral changes, suggesting that antagonism of AMPA receptors by the R isomer and stimulation of mGluR8 by the S isomer do not act synergistically on aggression in the racemic form of 3,4-DCPG.

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.

Pharmacological differentiation of kainate receptors on neonatal rat spinal motoneurones and dorsal roots.[Pubmed:9849660]

Neuropharmacology. 1998 Oct-Nov;37(10-11):1223-37.

The objectives of this study, conducted on neonatal rat spinal cord and dorsal roots in vitro, were to characterise the actions of a range of willardiine analogues on GluR5-containing kainate receptors present in dorsal roots, to determine whether GluR5-containing receptors are also present on motoneurones, and to differentiate responses mediated by kainate receptors from those mediated by AMPA receptors on motoneurones. (S)-5-Trifluoromethyl-willardiine, (S)-5-iodowillardiine, (S)-5-iodo-6-azawillardiine and ATPA were found to be potent agonists of kainate receptors on dorsal roots (EC50 values 0.108 +/- 0.002, 0.127 +/- 0.010, 0.685 +/- 0.141 and 1.3 +/- 0.3 microM, respectively) being more potent but of lower efficacy than kainate (EC50 value 14.8 +/- 1.8 microM). (S)-5-Iodo-6-azawillardiine blocked kainate-induced depolarisations of the dorsal root, probably via its desensitising action. Kainate-induced responses of dorsal roots were weakly antagonised by (RS)-3,5-dicarboxyphenylglycine (DCPG) (apparent KD 1.5 +/- 0.4 mM). Kainate receptors containing GluR5 subunits do not appear to be present on motoneurones since (RS)-3,5-DCPG (1 mM) potentiated rather than antagonised kainate-induced depolarisations of motoneurones. Although (S)-5-iodowillardiine (a potent and selective agonist at GluR5-containing kainate receptors) depolarised motoneurones (EC50 value 5.8 +/- 0.6 microM), such depolarisations were antagonised by both (RS)-3,4- and (RS)-3,5-DCPG, which are selective AMPA receptor antagonists at motoneurones, showing a KD value of 73 microM (Schild slope, 0.96 +/- 0.09) and an apparent KD value of 123 +/- 38 microM, respectively. This accords with the previously reported activity of willardiine analogues at AMPA receptors. Since neither (RS)-3,4- nor (RS)-3,5-DCPG antagonised kainate-induced motoneuronal depolarisations but cyclothiazide enhanced and GYK153655 blocked these responses it is possible that a component of the kainate response may be mediated by a population of DCPG-insensitive AMPA receptors on motoneurones. However, it is also possible that a population of kainate receptors other than those containing GluR5 subunits, are responsible for these effects. The new compounds introduced in this study are likely to be useful tools for studying the physiological role of kainate receptors in CNS function.

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.