Excitatory neurotransmission mediated by NMDA receptors plays a critical role in epilepsy and epileptogenesis. Blockers of the NMDA receptor- associated ion channel (uncompetitive antagonists), such as the dissociative anesthetics phencyclidine (PCP) and dizocilpine (MK-801), are powerful anticonvulsants. However side effects limit the utility of these drugs in the treatment of seizure disorders. Several dissociative anesthetic analogs that are effective anticonvulsants in animal seizure models but which have improved toxicity profiles compared to conventional dissociative anesthetic drugs have been identified. One of these is ADCI, a hybrid of dizocilpine and the widely used antiepileptic carbamazepine. (ADCI was discovered and its anticonvulsant activity was demonstrated at NIH; a patent covering ADCI as a composition of matter and its use in epilepsy therapy was issued to the Government and licensed to Neurogen Corporation. The drug is currently undergoing phase I clinical trials by the sub-licensee Wyeth-Ayerst Laboratories.) During the present reporting period, studies were conducted examining the interaction of ADCI with cloned NMDA receptor subunits expressed in HEK 293 cells using whole-cell voltage clamp recording. The objective of these studies was to examine the hypothesis that the improved toxicity profile of ADCI is related to subunit specificity in block of the NMDA receptor. ADCI exhibited significantly higher blocking potency for recombinant NMDA receptors composed of the NR1a/NR2B subunits than for NMDA receptors composed of the NR1a/NR2A or NR1a/NR2C subunits. NR2B selective NMDA receptor antagonists such as ifenprodil and eliprodil exhibit reduced toxicity in comparison with nonselective NMDA receptor antagonists. Similarly, the improved toxicity of ADCI may relate to its selectivity for NR2B-containing NMDA receptors. Dextromethorphan and its metabolite dextrorphan are low-affinity NMDA receptor antagonists with reduced toxicity in comparison with other channel blocking NMDA receptor antagonists. A series of 3- and 17- substituted analogs of dextromethorphan and dextrorphan were examined for anticonvulsant activity with the objective of identifying analogs with improved toxicity profiles. The structural analogs exhibited potent anticonvulsant activity in the mouse maximal electroshock seizure test, protected mice against NMDA-induced seizures and lethality, and also inhibited equilibrium [3-H]dizocilpine binding to NMDA receptor in rat forebrain membranes. The rank order of potencies in the binding assay was similar to that in the anticonvulsant screening tests, suggesting that the anticonvulsant activity of these analogs is likely to be mediated via NMDA receptor antagonism. Several of the analogs appeared to have improved toxicity profiles in comparison with the parent compounds. However, at high doses, the analogs produced lethality in mice indicating that their therapeutic potential may be limited.
