SIGMA RECEPTORS

西格玛受体

• 批准号: 3853721
• 负责人: T P SU
• 金额: --
• 依托单位: NATIONAL INSTITUTE ON DRUG ABUSE
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3853721
• 关键词: anticonvulsants; antipsychotic agents; brain imaging /visualization /scanning; chemical binding; computer simulation; conformation; dentate nucleus; electrophysiology; gel filtration chromatography; guinea pigs; haloperidol; laboratory mouse; ligands; molecular dynamics; molecular site; neuroanatomy; opioid receptor; potassium channel; progesterone; protein purification; receptor binding; schizophrenia; single photon emission computed tomography; temporal lobe /cortex

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.

该项目检查分子、电生理学和体内 西格玛（s）受体配体的相互作用。 统一的假设 用于结合 s 配体，包括类固醇、“非典型”抗精神病药、 例如 BMY-14802 和瑞莫必利，以及最具选择性的 s 配体， PRE-084，采用构象拟合和静电配制 潜在的计算。 所有 s 配体都有一个药效团，其中包含三个 互动场所；站点之间的距离是相同的 配体。 静电荷的表面图也类似 测试了所有 s 配体。 溶解的 s 受体被标记为 [3H]黄体酮，首次直接展示类固醇 与受体结合。 可溶性 s 受体也受以下因素调节 某些抗惊厥药物。 分子的初步估计 使用分子大小测定获得溶解的 s 受体的重量 色谱法。 调节关闭的低亲和力 s 受体 NCB-20 细胞中显示出强效钾通道。 低 亲和受体可能发挥重要的生理和药理作用 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 颞叶皮层和齿状体中 s 受体的选择性丧失 小脑核，表明 s 受体在 精神病，并强调 s 受体成像的重要性 体内。 对小鼠的研究表明，放射性标记 d-N-烯丙基正甲佐辛和氟哌啶醇显示出开发潜力 体内配体。 [125I]对碘苯基结合的研究 金刚烷胍 (PIPAG)，一种潜在的 SPECT 配体，对豚鼠脑的作用 显示出高亲和力 (0.6 nM) 和药理学特征 典型的经典 s 受体的神经解剖学分布。 未来的工作包括对其他配体的分子建模研究， PRE-084 的进一步化学和药理学研究，纯化 s受体及其调节机制的生化研究 补钾通道上的低亲和力 s 受体。