PCP RECEPTOR CHARACTERIZATION WITH NEW AFFINITY LIGANDS

苯环己哌啶（PCP）是一种广泛滥用的药物。 五氯苯酚的主要作用部位 脑中的PCP受体是N-甲基-D-天冬氨酸的一部分， （NMDA）受体/离子通道复合物。 五氯苯酚通过与五氯苯酚受体结合， 阻断由NMDA受体激动剂打开的阳离子通道。 甘氨酸， 通过与通道复合物上士的宁不敏感受体结合， 通过NMDA激动剂促进通道开放。 迫切需要 鉴定和表征PCP/NMDA/甘氨酸受体/通道蛋白。 目前，这些问题的特征不明确。 为了表征 蛋白质，必须开发高度特异性的受体配体。 在这 应用我们提出开发新的PCP和NMDA受体配体 和光亲和性放射性标记。 新的PCP受体活性药物和 亲和配体衍生自强效和选择性药物MK 801， 从我们实验室开发的两种新药IDDC和N，N '- 二萘基胍（DNG）。 将利用计算机建模来开发 还有其它新的PCP受体（亲和性）配体。 拟定亲和标记 对于NMDA结合位点的选择是基于拮抗剂CPP。 小说， 放射性标记的亲和探针将用于表征PCP和NMDA 与PCP/NMDA/甘氨酸受体离子相关的结合蛋白 通道复合体 为了表征[3 H]-甘氨酸结合蛋白 PCP/NMDA/甘氨酸受体复合物的亚基组成模型， 阐明PCP位点的药效团。 亲和受体 从而为最终的基因克隆奠定了基础 编码受体/离子通道复合物。 详细分析 PCP/NMDA/甘氨酸受体的分子结构是更好地 了解五氯苯酚滥用的分子基础并设计治疗方法 战略布局

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.