Suppression of audiogenic seizures in DBA/2 mice by two new dipeptide NMDA receptor antagonists

Two new phosphonate dipeptides, gamma-D- glutamylaminomethylphosphonate (Glu-Amp) and beta-D- aspartylaminomethylphosphonate (Asp-Amp), that are antagonists of excitation due to N-methyl-D-aspartate have been compared with omega-phosphonic-alpha-carboxylic amino acids as anticonvulsant agents in mice with sound-induced seizures. Compounds were injected intracerebroventricularly (i.c.v.) or intraperitoneally (i.p.) into DBA/2 mice 45 min prior to sound exposure, and ED50 values for suppression of the different phases of the seizure response were estimated. With i.c.v. injection Glu-Amp is 0.4-0.8 times as potent an anticonvulsant as (+/-)2-amino-7- phosphonoheptanoate and Asp-Amp is 1.3-2.5 times as potent. With i.p. injection Glu-Amp is 0.15-0.28 and Asp-Amp 0.23-0.58 times as potent as (+/-)2-amino-7-phosphonoheptanoic acid. These findings correspond to their known potency as N-methyl-D-aspartate antagonists, and are consistent with an anticonvulsant effect arising from action at a receptor sensitive to N-methyl-D-aspartate.