BIOLOGICAL AND BIOCHEMICAL CHARACTERIZATION OF "SIGMA RECEPTORS"

这个项目描绘了生物化学、化学和药理学 σ受体和配体的性质。 构象分析 σ配体的结构揭示了共同的药效团， 由三个假设点组成。 新的选择性sigma药物，如 如PRE-084、Remoxipride和BMY-14802，发现具有这种 药效团 静电势（ESP）的计算 配体产生了以下共同模式：最高ESP是 分布在分子的中心，最低的ESP在周围 外围。 这些结果可能有助于设计更具选择性的西格玛 用于治疗用途的配体。 在这个实验室发现的σ受体亚型， 结合配体的多种作用的比较和检验， 已经表明sigma-1和sigma-2受体可能具有单独的 功能协调发展的 在这个实验室里发现了一种新的，选择性的σ配体， 第084章正在调查中 使用匀浆结合试验，发现σ-1和σ-2受体 在大鼠脑的解剖区域中分布差异。 两种受体选择性标记的条件 现在正在建立大鼠脑切片， 这些受体的解剖位置通过受体的可视化 放射自显影 σ受体已经从膜上溶解，并且溶解的σ受体已经从膜上溶解。 受体已被分离成两种组分， 层析 受体的进一步纯化正在进行中。

This project delineates biochemical, chemical, and pharmacological properties of sigma receptors and ligands. Conformational analysis of the structures of sigma ligands have revealed a common pharmacophore, consisting of three hypothetical points. New selective sigma drugs, such as PRE-084, remoxipride and BMY-14802, were found to possess such a pharmacophore. Calculation of the electrostatic potential (ESP) on sigma ligands has generated the following common pattern: highest ESP is distributed in the center of the molecules, and the lowest ESP is around the periphery. These results may help design more selective sigma ligands for therapeutic usage. The discovery of sigma receptor subtypes in this laboratory, taken together with a comparison and examination of many actions of a ligands, have suggested that sigma-1 and sigma-2 receptors may have separate functions. A new, selective sigma ligand discovered in this laboratory, PRE-084, is under investigation. Using homogenate binding assays, sigma-1 and sigma-2 receptors were found to be distributed differentially among dissected regions of rat brain. Conditions for the selective labeling of the two types of a receptors in rat brain slices are now being established in order to allow precise visualization of anatomical location of these receptors via receptor autoradiography. Sigma receptors have been solubilized from membranes, and the solubilized receptors have been separated into two components with charge partition chromatography. Further purification of the receptors is underway.