[Comparative study of the NMDA-blocking activity and safety of mono- and bis-cationic compounds in animals]

Experiments on intact mice and rats showed that the monoammonium adamantyl-containing compounds memantine, amantadine, and IEM-1958 (an N-propyl amantadine analog) are capable of blocking the NMDA receptors and producing the anticonvulsant and antihypoxant effects in the case of a systemic administration in doses close to toxic. The acute toxicity of these compounds upon intraperitoneal injections to mice is manifested in doses only 2-8 times the minimum effective dose level. The bis-cationic compounds (arcaine, IEM-1464, and IEM 1490) containing two identical cation groups, exhibit a more pronounced activity and higher safety as compared to those of their monocationic counterparts. This is explained by the ability of the bis-cationic compounds to block a polyamine site of the NMDA receptor. Arcaine (the polyamine site blocker) and IEM-1464 produce the NMDA-receptor-blocking effect and exhibit the anticonvulsant and antihypoxant activity in doses 5-10 times smaller as compared to the effective dose of memantine. At the same time, arcaine is 5 times less toxic than memantine. The bis-adamantyl derivative IEM-13490 is 100-150 times more active and has a 139 times greater therapeutic ratio than memantine.