Neuropharmacology 40 (2001) 732–735 www.elsevier.com/locate/neuropharm Rapid communication Anticonvulsant activity of 3,4-dicarboxyphenylglycines in DBA/2 mice Randal X. Moldrich a , Philip M. Beart a , David E. Jane b , Astrid G. Chapman c , Brian S. Meldrum c,* a Department of Pharmacology, Monash University, Melbourne, Victoria, 3800, Australia b Department of Pharmacology, School of Medical Sciences, University of Bristol, Bristol BS8 1TD, UK c Department of Neurology, Institute of Psychiatry, Kings College, London, De Crespigny Park, Denmark Hill, London SE5 8AF, UK Received 10 October 2000; received in revised form 4 December 2000; accepted 8 December 2000 Abstract 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.  2001 Elsevier Science Ltd. All rights reserved. Keywords: Anticonvulsant; 3,4-dicarboxyphenylglycine (3,4-DCPG); (RS)-4-phosphonophenylglycine (RS)-PPG; DBA/2 mice; Epilepsy; mGluRs The 3,4-dicarboxyphenylglycines (3,4-DCPG) rep- resent a novel group of pharmacological tools which allow the investigation of the role of glutamate receptors in physiological and pathological conditions. The R- iso- mer of 3,4-DCPG has been identified as an AMPA receptor antagonist with weak activity at NMDA recep- tors and little, or no, activity at kainate receptors (Thomas et al., 1997). More recently, the S- isomer has been tested on cloned human metabotropic glutamate receptor (mGlu) subtypes and was identified as a selec- tive and full mGlu 8 agonist with weak activity at other mGlu receptor subtypes (Thomas et al., 2001). (S)-3,4- DCPG is at least 100-fold more potent at mGlu 8 than other group III mGlu receptors with the following order of potency mGlu 8 mGlu 6 mGlu 4 mGlu 7 . Both (RS)- and (S)-3,4-DCPG display weak or no antagonism of NMDA or kainate receptors. A similar functional pro- file of the compounds has been demonstrated in neonatal rat spinal cord (Thomas et al., 1997, 2001). Group III mGlu and AMPA receptors have been ident- * Corresponding author. Tel.: +44-207-8480398; fax: +44-207- 8480689. E-mail address: brian.meldrum@kcl.ac.uk (B.S. Meldrum). 0028-3908/01/$ - see front matter  2001 Elsevier Science Ltd. All rights reserved. PII:S0028-3908(01)00002-8 ified as targets for the suppression of epileptic seizures due to their ability to modulate glutamatergic neuro- transmission (Bleakman and Lodge, 1998; Cartmell and Schoepp, 2000). Previous studies have identified group III mGlu receptor agonists as potent inhibitors of sound- induced clonic-tonic seizures in mice and rats following intracerebral injection (Ghauri et al., 1996; Chapman et al., 1999). However, these agonists either induce procon- vulsant activity at higher doses or are not anticonvulsant when administered systemically. Alternatively, AMPA receptor antagonists are potent inhibitors of seizures induced in a variety of animal models (Chapman et al., 1991; Meldrum et al., 1992). The present study evalu- ated the anticonvulsant activity of the (R)-3,4-DCPG, (S)-3,4-DCPG and (RS)-3,4-DCPG against sound- induced clonic-tonic seizures induced in mice and inves- tigated the mechanism behind the potent anticonvulsant activity of (RS)-3,4-DCPG. All regulated procedures performed in this study were carried out in accordance with the UK Animals (Scientific Procedures) Act, 1986. Dilute brown agouti (DBA/2) mice (male and female, age 21–28 days, 7–15 g weight; Institute of Psychiatry colony and Harlan and Olac, Bichester, UK) undergo a well-characterised seiz- ure response when exposed to a loud stimulus. Drug or