PCP RECEPTOR CHARACTERIZATION WITH NEW AFFINITY LIGANDS

苯环利定(PCP)是一种被广泛滥用的药物。五氯苯酚的主要作用部位 大脑中的PCP受体是N-甲基-D-天冬氨酸的一部分 (NMDA)受体/离子通道复合体。PCP，通过与PCP受体结合， 阻断NMDA受体激动剂开放的阳离子通道。甘氨酸， 通过与通道复合体上的士的宁不敏感受体结合， 促进NMDA激动剂的通道开放。有迫切的需要 鉴定和鉴定PCP/NMDA/甘氨酸受体/通道蛋白。 目前，这些问题的特点并不明确。为了更好地描述 蛋白质，高度特异性的受体配体必须开发。在这件事上 我们建议开发新的PCP和NMDA受体配体的应用 和光亲和放射性标记。新型PCP受体活性药物和 亲和配体来源于强效和选择性药物MK801和 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 还有其他新的PCP受体(亲和力)配体。建议的亲和标签 对于NMDA的结合部位是以拮抗剂CPP为基础的。这部小说， 将使用放射性标记的亲和探针来表征PCP和NMDA 五氯酚/N-甲基-D-天冬氨酸/甘氨酸受体相关结合蛋白(S) 航道综合体。为了鉴定[~3H]-甘氨酸结合蛋白 PCP/NMDA/甘氨酸受体复合体的亚基组成模型及TO 阐明PCP位点的药效团。亲和力受体 蛋白质(S)，从而为最终克隆基因奠定了基础 编码受体/离子通道复合体。详细分析了 PCP/NMDA/甘氨酸受体的分子结构对于更好地 了解五氯苯酚滥用的分子基础并设计治疗方法 战略。

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.