SYNTHESIS AND PHARMACOLOGICAL EVALUATION OF A SERIES OF DIBENZO[A,D]CYCLOALKENIMINES AS N-METHYL-D-ASPARTATE ANTAGONISTS

A series of 73 dibenzo[a,d]cycloalkenimines were synthesized and evaluated for their ability to displace (+)-10, 11-dihydro-5-methyl-5H-dibenzo[a,d]cyclohepten-5,10-imine ([3H]-(+)-10) from its specific binding site on rat cortical membranes. A number of the more active compounds (Kiranging from 0.006 to 0.21 μM) were evaluated for N-methyl-D-aspartate (NMDA) antagonist activity in the rat cortical slice (Kbranging from 0.08 to 0.9 μM) and anticonvulsant activity in the mouse against NMDA induced convulsions. The ED50values ranged from 0.22 to 7.76 mg/kg and correlated reasonably well with the Kbdetermination. In the dibenzo[a,d]cyclohepten-5,10-imine series, the (+)-5S,10R enantiomer displayed consistently higher levels 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. © 1990, American Chemical Society. All rights reserved.