Comparison of the effects of cholinesterase inhibitors on [H-3]MK-801 binding in rat cerebral cortex

Huperzine A, a selective inhibitor of acetylcholinesterase, was recently de monstrated to exert an antagonist effect on N-methyl-D-aspartate (NMDA) rec eptor in rat cerebral cortex. In the present study, the effects of six chol inesterase inhibitors, e.g, huperzine A, huperzine B, tacrine, donepezil (E 2020), physostigmine and galanthamine on [H-3]dizocilpine (MK-801) binding to synaptic membrane of rat cerebral cortex were compared. Their IC50 value s (mean +/- SD) were 36.9 +/- 12.1, 316.8 +/- 93.2, 33.2 +/- 3.7, 135.0 +/- 15.1, 50.4 +/- 7.4, and 3344 +/- 295 mu M, respectively. The rank order of potency is tacrine approximate to huperzine A > physostigmine > donepezil > huperzine B >> galanthamine. There is no correlation between their activi ties to inhibit [H-3]MK-801 binding and to inhibit acetylcholinesterase (r = +0.563, P = 0.245). The results suggest that most cholinesterase inhibito rs available exhibit an antagonist effect on NMDA receptor in rat cerebral cortex in addition to their inhibitory effect on acetylcholinesterase. (C) 1999 Elsevier Science Ireland Ltd. All rights reserved.