[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.
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Anichkov Department of Neuropharmacology, Institute of Experimental Medicine, Russian Academy of Medical Sciences, ul. Akad. Pavlova 12, St. Petersburg, 197022 Russia.
Serdiuk
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D000818:Animals; D000927:Anticonvulsants / Q000009:adverse effects / Q000494:pharmacology / Q000633:toxicity; D002413:Cations, Divalent; D002414:Cations, Monovalent; D018691:Excitatory Amino Acid Antagonists / Q000009:adverse effects / Q000494:pharmacology* / Q000633:toxicity; D000860:Hypoxia / Q000139:chemically induced / Q000188:drug therapy; D007928:Lethal Dose 50; D008297:Male; D051379:Mice; D010147:Pain Measurement; D051381:Rats; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D012977:Sodium Nitrite; D013329:Structure-Activity Relationship
D000927:Anticonvulsants; D002413:Cations, Divalent; D002414:Cations, Monovalent; D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; D012977:Sodium Nitrite
Sravnitel'nyĭ analiz NMDA-blokiruiushcheĭ aktivnosti i bezopasnosti mono-kationnykh i bis-kationnykh soedienniĭ v opytakh na zhivotnykh.