Phencyclidine (PCP) is a widely abused drug. A major site of action of PCP in brain is the PCP receptor that is part of the N-methyl-D-aspartate (NMDA) receptor/ion channel complex. PCP, by binding to PCP receptors, blocks a cation channel that is opened by NMDA receptor agonists. Glycine, by binding to a strychnine-insensitive receptor on the channel complex, facilitates channel opening by NMDA agonists. There is an urgent need to identify and characterize the PCP/NMDA/glycine receptor/channel proteins. These are currently poorly characterized. In order to characterize the proteins, highly specific receptor ligands must be developed. IN this application we are proposing to develop novel PCP and NMDA receptor ligands and photoaffinity radiolabels. The novel PCP receptor active drugs and affinity ligands are derived from the potent and selective drug MK801 and from two novel drugs developed in our laboratories, IDDC and N,N'- dinaphthyl-guanidine (DNG). Computer modelling will be utilized to develop yet other novel PCP receptor (affinity) ligands. Proposed affinity labels for the NMDA binding site are based on the antagonist CPP. The novel, radiolabelled affinity probes will be used to characterize the PCP and NMDA binding protein(s) associated with the PCP/NMDA/glycine receptor ion channel complex. In order to characterize the [3H]-glycine binding protein subunit composition model of the PCP/NMDA/glycine receptor complex and to elucidate the pharmacophore of the PCP-site. The affinity receptor protein(s) thus laying the groundwork for eventual cloning of the genes coding for the receptor/ion channel complex. A detailed analysis of the molecular structure of PCP/NMDA/glycine receptors is necessary to better understand the molecular basis of PCP abuse and to devise treatment strategies.
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