Synthesis and Study of Anticonvulsant, Anti-Ischemic, and Antihypoxic Activity of NMDA and AMPA Dicationic Adamantane-Containing Open Channel Blockers In Vitro and In Vivo

Experiments (patch-clamp) in vivo and in vitro revealed two groups in a series of dicationic compounds with adamantane-containing radicals that selectively blocked NMDA (N-methyl-D-aspartate) and AMPA (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid) receptors. Compounds of the first group containing an unsubstituted amino group (IEM-1754 and IEM-1755) in experiments in vivo showed the properties of selective NMDAantagonists, while substances of the second group containing a quaternary ammonium group with a stable (+)-charge (IEM-1553, IEM-1751, IEM-1857, and IEM-2324) showed the properties of selective AMPA antagonists. IEM-2324 showed the highest AMPA activity and selectivity and was 13 times more active than the reference AMPA antagonist IEM-1460 in terms of AMPA blocking activity (IC₅₀ 0.22 and 3 M, respectively) and 7.5 times more active in terms of AMPAselectivity (101 and 763 times, respectively). Selective NMDA antagonists of the first group and reference compounds MK-801 and memantine had anticonvulsant, anti-ischemic and antihypoxic effects and prevented lethality caused by toxic doses of NMDA. Selective AMPA antagonists of the second group and reference drug DNQX had anticonvulsant, anti-ischemic and antihypoxic effects, but did not prevent lethality caused by toxic doses of NMDA. The NMDAantagonist IEM-1754 had the highest activity. which exceeded MK-801 by 5–10 times in activity and memantine by 300- 800 times in all test subjects. Acorrelation was established between the channel-blocking activity of the NMDA antagonists and their pharmacological activity in in vivo experiments.