BIOLOGICAL AND BIOCHEMICAL CHARACTERIZATION OF "SIGMA RECEPTORS"

这个项目描述了生化、化学和药理学。 Sigma受体和配体的性质。构象分析 西格玛配体的结构揭示了一个共同的药效团， 由三个假设点组成的。新的选择性西格玛药物，如 与084年之前一样，REMOXPride和BMY-14802被发现具有这样的 药效团。Sigma上静电势(ESP)的计算 配体产生了以下常见模式：最高ESP是 分布在分子的中心，最低的ESP在 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。 本实验室发现的Sigma受体亚型 结合对配体的许多作用的比较和检验， 提示Sigma-1和Sigma-2受体可能有不同的 功能。在这个实验室中发现了一种新的选择性西格玛配体， Pre-084，正在接受调查。 通过匀浆结合分析，发现了Sigma-1和Sigma-2受体 在大鼠大脑的不同解剖区域中有不同的分布。 两种受体选择性标记的条件 现在正在建立大鼠脑片，以便能够准确地 通过受体显示这些受体的解剖位置 放射自显影。 Sigma受体已经从膜上增溶，而增溶的 受体通过电荷分配被分成两个组分 层析法。对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.