ADCI (5-aminocarbonyl-5H-dibenzo[a,d]cyclohepten-5,10-imine), a low affinity noncompetitive NMDA antagonist, was resolved into its optical enantiomers. (+)-ADCI was approximately twice as potent an anticonvulsant in the maximal electroshock (MES) test as (-)-ADCI and had a somewhat higher therapeutic index, suggesting that the (+) enantimer may be more appropriate for further clinical development than the racemate. (+/-)- ADCI was highly effective in preventing the occurrence of seizures and tremulousness in mice made physically dependent upon ethanol. Thus, ADCI may be therapeutically useful for treating ethanol withdrawal seizures and other aspects of the ethanol withdrawal syndrome. The ability of various anticonvulsant drugs to protect against seizures produced by K+ channel blocking agents was evaluated in mice. Seizures were induced by intraperitoneal 4-aminopyridine (4-AP) or intraventricular dendrotoxin, a K+ channel blocking peptide. Phenytoin, carbamazepine and other phenytoin-like anticonvulsant drugs were effective in these models, but many other anticonvulsant drugs were inactive. ADCI was also highly effective in protecting against both 4-AP and dendrotoxin seizures. The muscarinic antagonists atropine and scopolamine were found to attenuate the increased locomotor activity produced by the noncompetitive NMDA antagonist dizocilpine. Muscarinic blockade is a potential strategy for preventing the adverse effects of NMDA antagonists. A series of 4-amino- (N-1-arylcycloalkyl)-benzamides were evaluated for anticonvulsant activity in the mouse MES test. 4-Amino-N-(1-phenyl)cyclohexyl-benzamide was found to have a particularly favorable therapeutic index.
