N-Allylnormetazocine (SKF 10,047)

Low Affinity

Dextromethorphan Memantine Amantadine

Ramacemide (FPL-12924)

ARL-15896 (AR-R15896) ADCI Ibogaine

Marketed—cough suppression; Prior investigation—stroke Marketed (Europe)—dementia Marketed—influenza, Parkinson's disease Prior development—epilepsy, stroke

In development—Huntington's disease, Parkinson's disease In development—stroke Prior investigation—epilepsy In development—drug dependence

(Fig. 4), stereotypies, and disruptions in learning and memory (cf. ref. 15 and 16). These compounds also produce subjective effects as assessed in drug discrimination paradigms that are similar to those of PCP. Such PCP-like discriminative stimulus effects generally correlate with affinity for the NMDA-receptor ion channel (8,17-19). Importantly, the diverse behavioral actions of dissociative anestheticlike uncompetitive NMDA antagonists occur at doses that are predicted to produce clinical efficacy. Thus, such agents are expected to exhibit little separation between clinical efficacy and side effects.

Clinical experience with PCP, ketamine, dizocilpine, and aptiganal has indeed provided evidence of poor tolerability. These agents all induce troubling behavioral side effects, including hallucinations, poor concentration, ataxia, sedation, depression, and other symptoms resembling those of schizophrenia (20,21). As PCP is a highly abused substance, drug abuse is an additional concern with respect to the clinical use of drugs in this class. In addition, uncompetitive blockers of the NMDA receptor may cause cellular toxicity, including neuronal vacuolization at low doses (22) and necrosis at higher doses (23). However, the generality of these findings to primates may be limited and it is now apparent that some NMDA antagonists produce, if anything, only transient vacuolization without necrosis.

A second major class of channel-blocking NMDA receptor antagonists are the low-affinity uncom-petitive antagonists that are in clinical practice, in advanced stages of clinical trials, or in other phases of development for a host of neurological indications (24). (Table 1). ADCI and memantine are two members of this class of drugs, which generally have more favorable side-effect profiles in comparison with dissociative anestheticlike agents (25-27). For example, ADCI exhibits a large separation (18fold) between its potency to block cocaine-induced seizures and its potency to produce neurological impairment, which contrasts dramatically with the situation for dizocilpine in which impairment occurs at 50% of the dose required for seizure protection (13). ADCI also suppressed withdrawal seizures in mice physically dependent on ethanol and produces anticataleptic effects at doses that do not produce ataxia, stereotypy, or impairment of locomotion (27,28). Similarly, memantine blocks NMDA-induced convulsions at doses that are 8- to 18-fold lower than those producing ataxia or effects on locomotion; in contrast, the anticonvulsant activity of dizocilpine is evident only at behaviorally

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