DEVELOPMENT OF SELECTIVE PCP RECEPTOR LIGANDS

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Phencyclidine (PCP) was introduced into clinical practice in 1958 as a potent, fast-acting anesthetic that did not cause respiratory depression. However, its medical usefulness was limited due to psychotomimetic side effects, and it was withdrawn from medical use in 1965. Since PCP is sometimes euphorigenic, it became a major drug of abuse. Studies directed toward understanding PCP's mechanism of action led to the identification of specific PCP binding sites. While the original studies suggested that the PCP binding site was a single entity, further studies have shown "PCP receptors" represent multiple binding sites. At present there are at least three significant classes of "PCP receptors": 1) PCP/NMDA-coupled receptors; 2) sigma receptors; and 3) PCP-dopamine reuptake carriers. The specific aim of the research proposed in this application is to discover and develop compounds specific for the PCP/NMDA-coupled receptor. In order to achieve this goal, we have used molecular modeling techniques to identify four classes of geometrically rigid tricyclic benzylic amines that fit the PCP/NMDA pharmacophore model that we have proposed. Since MK801 shows the greatest difference between PCP/NMDA-coupled and PCP- dopamine reuptake carrier binding site, we tailored the compounds to allow exploration of the structural differences between the structures of MK801 and PCP. The structure-activity relationship information from this study will establish further the PCP receptor subtype concept and will be helpful for the future design of more selective drugs. PCP ligands selective for only the PCP/NMDA-coupled site might be free of psychoactive side effects and might be useful for the treatment of disorders involving this receptor.