title: Anticonvulsant activity of two novel piperazine derivatives with potent kainate antagonist activity.
abstract: Two dicarboxylic piperazine derivatives, 1-(p-chlorobenzoyl)-piperazine-2,3-dicarboxylic acid (pCB-PzDA) and 1-(p-bromobenzoyl)-piperazine-2,3-dicarboxylic acid (pBB-PzDA), that block excitation at glutamate receptors have been evaluated as anticonvulsants in rodent models of epilepsy by i.c.v. or i.p. injection. In DBA/2 mice, pBB-PzDA (0.01 mumol i.c.v.) or pCB-PzDA (0.03 mumol i.c.v.) protects against the clonic and tonic seizures induced by loud sound. Protection is also seen following i.p. injection of pBB-PzDA (0.33-1.0 mmol/kg) or pCB-PzDA (0.66-1.0 mmol/kg). In Swiss S mice suppression of seizure activity induced by i.c.v. injection of excitatory amino acid agonists shows that both compounds are preferentially active against alpha-kainate, with the following rank orders (for pBB-PzDA); alpha-kainate greater than quisqualate greater than N-methyl-D-aspartate greater than quinolinate greater than L-glutamate; and (for pCB-PzDA): alpha-kainate greater than quinolinate greater than N-methyl-D-aspartate greater than quisqualate greater than L-glutamate. These compounds are the most potent preferential alpha-kainate antagonists so far tested. The relationship between antagonism at the various receptor subtypes and anticonvulsant action is not adequately defined.
mesh_terms: D000161:Acoustic Stimulation; D000818:Animals; D000927:Anticonvulsants / Q000627:therapeutic use*; D001224:Aspartic Acid / Q000031:analogs & derivatives; D055598:Chemical Phenomena; D002621:Chemistry; D005971:Glutamates; D007608:Kainic Acid / Q000037:antagonists & inhibitors*; D051379:Mice; D008811:Mice, Inbred DBA; D008815:Mice, Inbred Strains; D016202:N-Methylaspartate; D010069:Oxadiazoles; D010879:Piperazines / Q000627:therapeutic use*; D011759:Pyrrolidines / Q000037:antagonists & inhibitors*; D011805:Quinolinic Acids; D016318:Quisqualic Acid; D012640:Seizures / Q000139:chemically induced / Q000517:prevention & control
chemical_list: D000927:Anticonvulsants; D005971:Glutamates; D010069:Oxadiazoles; D010879:Piperazines; D011759:Pyrrolidines; D011805:Quinolinic Acids; D001224:Aspartic Acid; D016202:N-Methylaspartate; D016318:Quisqualic Acid; C045882:1-(4-chlorobenzoyl)piperazine-2,3-dicarboxylic acid; C045883:1-(4-bromobenzoyl)piperazine-2,3-dicarboxylic acid; D007608:Kainic Acid