SIGMA RECEPTORS

该项目研究分子、电生理和活体。 Sigma(S)受体的配体相互作用。统一的假说 对于S配体的结合，包括类固醇，“非典型”抗精神病药物， 如BMY-14802和RemoxiPride，以及最具选择性的S配体， Pre-084，通过构象拟合和静电作用形成 潜在的计算。所有的S配体都有一个药效团，有三个 交互站点；站点之间的距离对于 配基。静电电荷的曲面贴图也类似于 所有的S配体都进行了测试。溶解的S受体被标记 黄体酮，提供类固醇的第一个直接证明 与受体结合。溶解的S受体也是由 某些抗惊厥药物。分子的初步估算 用分子测定法测定了S受体的增溶质量 层析法。调节细胞关闭的低亲和力S受体 NCB-20细胞存在紧张性钾通道。低谷 亲和力受体可能发挥重要的生理和药理作用 在运动调节中的作用。 对精神分裂症患者死后大脑的研究表明 颞叶皮质和齿状回S受体的选择性丢失 小脑核，提示S受体在脑内的作用。 并强调了对S受体进行成像的重要性 活着。在老鼠身上的研究表明，放射性标记 D-N-烯丙基去甲氧嘧啶和氟哌啶醇具有开发潜力 体内配体。[125I]对碘苯基的结合作用研究 一种潜在的豚鼠脑SPECT配体--金刚烷基胍 显示出高亲和力(0.6 NM)和药理特性 经典S受体典型的神经解剖学分布。 未来的工作包括对其他S配体的分子模拟研究， Pre-084的进一步化学和药理研究，纯化 S受体及其调控机制的生化研究 紧张性钾通道上的低亲和力S受体。

This project examines molecular, electrophysiological, and in vivo interactions of ligands for sigma (s) receptors. A unifying hypothesis for binding of s ligands, including steroids, "atypical" antipsychotics, such as BMY-14802 and remoxipride, and the most selective s ligand, PRE-084, was formulated using conformational fitting and electrostatic potential calculations. All s ligands have a pharmacophore with three sites of interaction; the distances between the sites are identical for the ligands. Surface maps of electrostatic charges also are similar for all s ligands tested. Solubilized s receptors were labeled with [3H]progesterone, providing the first direct demonstration of steroid binding to the receptors. Solubilized s receptors also are modulated by certain anticonvulsant drugs. A preliminary estimation of the molecular weight of solubilized s receptors was obtained using molecular sizing chromatography. A low affinity s receptor that modulates the closing of a tonic potassium channel was demonstrated in the NCB-20 cells. The low affinity receptor may play an important physiological and pharmacological role in locomotion regulation. Studies of postmortem brains from schizophrenic patients demonstrated selective losses of s receptors in the temporal cortex and dentate nucleus of the cerebellum, suggesting a role of the s receptor in psychosis, and underscoring the importance of imaging the s receptor in vivo. Studies in mice indicated, that radiolabeled d-N-allylnormetazocine and haloperidol show potential to be developed as in vivo ligands. Studies of the binding of [125I]p-iodophenyl amanantylguanidine (PIPAG), a potential SPECT ligand, to guinea pig brain showed high affinity (0.6 nM) and a pharmacological profile and neuroanatomical distribution typical of the classical s receptor. Future work includes molecular modeling studies on other s ligands, further chemical and pharmacological studies of PRE-084, purification of s receptors, and biochemical studies on the mechanism of modulation of the low affinity s receptor on the tonic potassium channel.