Plasma levels of ADCI (5~aminocarbonyl~5H~dibenzo[a,d]cyclohepten~5,10~imine), a low~affinity uncom~petitive NMDA antagonist currently under development for use in epilepsy therapy, were determined using gas chromatography~mass spectroscopy following acute and chronic dosing in mice. At anti~convulsant doses, plasma levels were achieved that were within the range that produce substantial blockade of NDMA receptors (as determined in in vitro experiments). Following chronic (2 wk) ad~ministration of ADCI, mice exhibited tolerance to the anticonvulsant effects of the drug that could be overcome by raising the dose. This tolerance appeared to be due to induction of metabolism and not to pharmacodynamic factors since the blood levels achieved with the higher anticonvulsant doses in tolerant animals corresponded closely to the levels achieved in naive animals receiving an anticonvulsant dose. ADCI was resolved into its optical enantiomers. (+)~ADCI was approximately twice as potent an anticonvulsant in the maximal electroshock test as (~)~ADCI and had a somewhat higher therapeutic index, suggesting that the (+)~enantiomer may be more appropriate for further clinical development than the racemate. Drug discrimination studies in rats trained to discriminate dizocilpine from saline indicated that ADCI does not substitute for dizocilpine and that other low~affinity uncompetitive NMDA antagonists only weakly substitute for the drug. These results suggest that low~affinity uncompetitive NMDA antagonists may have a superior side effect profile than conventional NMDA antagonists, and support the potential utility of this class of compounds in epilepsy therapy. Dopamine receptor blockade with haloperidol, cis~flupenthixol (a combined D1 and D2 antagonist) or a combination of raclopride (a selective D1 antagonist) and SCH[23390 (a selective D2 antagonist) was found to attenuate the stimulation of locomotion induced by dizocilpine, indicating that dopamine receptor antagonists might be useful in preventing the adverse behavioral effects of uncompetitive NDMA antagonists.
