Synthesis and Pharmacological Properties of Adamantane-Containing Bis-Cationic Compounds

The bis-cationic compound 1-amino-4-(1-adamantanamino)butane dihydrochloride (IEM-1913) has important advantages over clinically employed monocationic 3,5-dimethyl-1-aminoadamantane (memantine) because its anticonvulsant activity is significantly greater and its therapeutic index is 814 times higher than that of memantine. 1-Amino-4-(3,5-dimethyl-1-adamantanamino)butane dihydrochloride (IEM-2127) and 1-amino-6-(3,5-dimethyl-1-adamantanamino)hexane dihydrochloride (IEM-2121) have anticonvulsant activity equal to that of memantine although their therapeutic indices are 94.9 and 88.6 times, respectively, greater than that of memantine. IEM-1913 causes statistically significant anticonvulsant effects in the dose range 0.03 – 0.3 mg/kg; IEM-2127 and IEM-2121, in the dose range 0.1 – 1.0 mg/kg, in contrast with memantine, which is effective only at a single maximum dose of 15 – 20 mg/kg. The high anticonvulsant activity and low toxicity of IEM-1913, IEM-2121, and IEM-2127 are explained by the fact that these bis-cationic compounds cause combined blocking of NMDA and AMPA brain receptors, in contrast with monocationic selective NMDA-blocker memantine.