For treatment of drug dependencies and associated toxicities, and the drug-abuse associated spread of HIV infection in AIDS, previous work by our group has demonstrated the potential for drug development in three major areas: low affinity NMDA antagonists, strychnine-insensitive glycine site antagonists, and benztropine. Having identified last year that ibogaine, a potential broad-based drug abuse therapeutic, was a low affinity NMDA receptor blocker, we have spent the current year identifying other low-affinity ligands that may have similar therapeutic efficacy but are devoid of the behavioral toxicity of ibogaine. We have identified, memantine, as a potential candidate for clinical trials based upon its current safe use in Parkinsonism and our preclinical findings of efficacy. Several analogs of dextromethorphan continue to be evaluated for efficacy and safety. So far, these compounds appear to display a broad margin of safety, compared with other NMDA receptor channel blockers. We have recently discovered a potential new class of compounds that selectively block the behavioral effects of phencylidine (PCP) and related psychotomimetic agents. PD 128,907 is the most selective drug discovered thus far that binds to dopamine D3 receptors. This compound, like the atypical antipsychotic, clozapine, dose- dependently blocks the behavioral effects of the selective PCP-site antagonist, dizocilpine. Like clozapine, PD 128,907 is only marginally effective against dopaminergically-driven behavioral toxicities. Thus, in addition to the potential role of D3 receptor agonists in the treatment of PCP-intoxication and toxicity, this is the first time the D3 receptor population has been directly shown to have relevance to the treatment of schizophrenia. Finally, we have begun work on a novel class of neuroactive steroids. We have shown that these compounds, like NMDA receptor blockers, can protect against the convulsant effects of cocaine that are relatively unresponsive to treatment by standard GABAmimetic drugs like diazepam or phenobarbital. Given the unique activity of these compounds and the previous suggestions that GABA agonists may be useful in the treatment of psychomotor stimulant abuse, we are currently gearing our work toward such an assessment.
