DRUG DEVELOPMENT OF SELECTIVE PCP RECEPTOR LIGANDS

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Phencyclidine (PCP) is a psychotomimetic drug that interacts with the N- methyl-D-aspartate (NMDA) excitatory amino acid receptor, cholinergic receptors, potassium channels, biogenic amine transporters (BAT), and sigma binding sites. Consistent with this broad array of central nervous system macromolecular targets, PCP has a complex pharmacology, including a strong abuse liability in humans. Many studies from several laboratories have demonstrated that most of the behavioral effects produced by low doses of PCP in animals result from the uncompetitive inhibition of the NMDA receptor. The potentially useful anticonvulsant and neuroprotective effects of the PCP class of compounds are also mediated by the NMDA receptor (PCP site 1). More recently, the possible usefulness of uncompetitive NMDA inhibitors in drug addiction was illustrated by reports of the ability of the NMDA uncompetitive inhibitor MK801 to block opioid tolerance and dependence. Unfortunately, the undesirable behavioral effects and neurological toxicity of MK801 overshadow its possible benefits. [3H]TCP has been shown to label a site (PCP site 2) associated with the biogenic amine transporter (BAT). BAT ligands are of interest since they have potential in treating various stages of cocaine addiction. During the present grant, we discovered three structurally novel classes of compounds that bind selectively to PCP site 2 with greater potency than any previously reported compounds. The major specific aim of this renewal application is the design, synthesis, and biological evaluation of PCP site 2 ligands. Such studies are needed to more fully characterize the site 2 pharmacophore and to learn more about the pharmacology of this site. A second aim is the design, synthesis, and biological evaluation of a class of NMDA uncompetitive inhibitors represented by (+/-)-5- aminocarbonyl- 10,11 -dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine (ADCI). In vitro studies have demonstrated that this class of inhibitors binds weakly as NMDA receptor-channel-blockers (uncompetitive antagonists) yet are potent anticonvulsants with low toxicity. The mechanism responsible is not clearly understood but will be addressed in this application. In order to accomplish the goals above, RTI has combined its major expertise, medicinal chemistry and organic synthesis, with three experts in the biochemical and pharmacological fields-Dr. Richard Rothman of NIDA (ARC) for radioligand binding and autoradiographic studies; Dr. Michael Rogawski of NIH for anticonvulsant and toxicity studies; and Dr. Robert Balster at MCV for drug discrimination studies. To supplement these efforts, additional information about the target compounds will be gained by submitting them to the CPDD (tolerance and withdrawal studies) and the cocaine treatment discovery program for further evaluation. The information gained from these studies could lead to the development of medications for the treatment of cocaine addiction as well as opiate tolerance and withdrawal.