Synthesis and Pharmacological Evaluation of a Series of Dibenzocycloalkenimines as N-Methyl-D-aspartate Antagonists

Article abstract of DOI:10.1021/jm00164a052

A series of 73 dibenzocycloalkenimines were synthesized and evaluated for their ability to displace (+)-10,11-dihydro-5-methyl-5H-dibenzocyclohepten-5,10-imine (<3H>-(+)-10) from its specific binding site on rat cortical membranes.A number of the more active compounds (K_i ranging from 0.006 to 0.21 μM) were evaluated for N-methyl-D-aspartate (NMDA) antagonist activity in the rat cortical slice (K_b ranging from 0.08 to 0.9 μM) and anticonvulsant activity in the mouse against NMDA induced convulsions.The ED₅₀ values ranged from 0.22 to 7.76 mg/kg and correlated reasonably well with the K_b determination.In the dibenzocyclohepten-5,10-imine series, the (+)-5S,10R enantiomer displayed consistently higher leves of biological activity.While substitution at the 3-position of (+)-10 with electronegative atoms generally increased in vitro activity, a loss of potency relative to (+)-10 (MK-801) was observed in vivo for all of the compounds tested.