Muscle relaxant and anticonvulsant activity of 3-((+/-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid, a novel N-methyl-D-aspartate antagonist, in rodents.

A novel 4-substituted derivative of piperazine-2-carboxylic acid, 3-((+/-)-2-carboxypiperazin-4-yl)-propyl-1-phosphonic acid (CPP), with potent N-methyl-D-aspartate (NMDA) antagonist activity was evaluated as a muscle relaxant in genetically spastic rats. CPP, 0.02-0.1 mmol/kg, given intraperitoneally reduced the tonic activity in the electromyogram recorded from the gastrocnemius muscle of genetically spastic rats in a dose- and time-dependent manner. Muscle relaxation was also seen following intrathecal application of CPP, 0.0002-0.002 mumol, in genetically spastic rats. CPP, 0.1 mmol/kg, while not affecting Hoffman (H-) reflexes, depressed flexor reflexes in anesthetized rats following intravenous administration. In mice, CPP, 0.001 mumol, given intracerebroventricularly preferentially antagonized myoclonic seizures induced by NMDA and quinolinate, and had no effect on convulsions elicited by kainate, quisqualate and L-glutamate. These observations identify CPP as the most potent preferential NMDA antagonist so far tested with muscle relaxant and anticonvulsant activity resembling the profile of action of 2-amino-7-phosphonoheptanoate.