Behavioral effects and anticonvulsant efficacies of low-affinity, uncompetitive NMDA antagonists in mice.
BACKGROUND
It has been hypothesized that low-affinity, uncompetitive N-methyl-d-aspartate (NMDA) antagonists may have therapeutic efficacy (e.g., in epilepsy, stroke, drug dependence) without the adverse side effects associated with high-affinity ligands (e.g., dizocilpine, phencyclidine).


OBJECTIVE
To determine whether low-affinity NMDA antagonists have a larger predicted therapeutic window than high-affinity ligands.


METHODS
In Swiss-Webster mice, we compared the effects of uncompetitive antagonists having a range of affinities for the NMDA receptor ion channel [dizocilpine, memantine, ibogaine, amantadine and 5-aminocarbonyl-10, 11-dihydro-5h-dibenzo[a,d] cyclohepten-5,10-imine (ADCI)] in three behavioral assays typically used to assess NMDA receptor antagonism. Behavioral side effects were compared with the efficacy of the compounds to protect against NMDA-induced seizures.


RESULTS
Only dizocilpine and memantine substituted fully in mice trained to discriminate dizocilpine from saline. Dizocilpine (K(i) approximately 0.003 microM) protected against NMDA-induced convulsions at doses that produced ataxia and stimulation of locomotor activity. Conversely, memantine (K(i) approximately 0.54 microM) prevented convulsions at doses that were 8- to 18-fold lower than those producing ataxia or effects on locomotion, respectively. Indeed, in contrast to dizocilpine, memantine did not stimulate locomotor activity but only produced dose-dependent reductions. The low-affinity antagonists ibogaine (K(i) approximately 1 microM) and ADCI (K(i) approximately 11 microM) protected against convulsions at doses that produced significant dizocilpine-like discriminative stimulus effects, ataxia and decreases in locomotor activity. Amantadine (K(i) approximately 11 microM) was ineffective against NMDA-induced convulsions up to doses that produced significant behavioral side effects.


CONCLUSIONS
These findings indicate that only certain low-affinity, uncompetitive NMDA antagonists (e.g., memantine) may have therapeutic efficacy at doses that do not produce an adverse side-effect profile. For other therapeutic endpoints, different estimates of efficacy and safety require derivation.
Geter-Douglass
B
B
Drug Development Group, NIDA Addiction Research Center, NIH, 5500 Nathan Shock Drive, Baltimore, MD 21224, USA.
Witkin
J M
JM
D000818:Animals; D000927:Anticonvulsants / Q000494:pharmacology*; D004193:Discrimination Learning / Q000187:drug effects*; D016291:Dizocilpine Maleate / Q000031:analogs & derivatives / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D007050:Ibogaine / Q000494:pharmacology; D008297:Male; D008559:Memantine / Q000494:pharmacology; D051379:Mice; D009043:Motor Activity / Q000187:drug effects*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*
D000927:Anticonvulsants; D018691:Excitatory Amino Acid Antagonists; D016194:Receptors, N-Methyl-D-Aspartate; C071316:5-aminocarbonyl-10,11-dihydro-5H-dibenzo(a,d)cyclohepten-5,10-imine; D007050:Ibogaine; D016291:Dizocilpine Maleate; D008559:Memantine