BIOLOGICAL AND BIOCHEMICAL CHARACTERIZATION OF SIGMA RECEPTORS

该项目描绘了生物化学和 σ受体和配体的药理学性质。在这 一个财政年度，我们发现，神经安定药舒必利可以增强 NMDA诱导的细胞内钙离子浓度升高， 舒必利的这种作用反过来又被σ配体增强。 此外，还发现舒必利的这种作用被蛋白质阻断 激酶A抑制剂。结果表明， 抗精神病药和σ配体的作用，并建议该作用 两种药物中的一种或两种都可以使细胞内钙离子 信号传导和蛋白磷酸化。从行为上看，我们发现， 合成的σ配体PRE-084，如神经甾体双烯醇酮 硫酸和二氢表雄酮，改善学习和记忆 在记忆能力被icv损害的小鼠中， 注射β-淀粉样肽25-35。此外，所有人的行动 有三种化合物被一种神经类固醇黄体酮阻断， 其结合σ受体。因此，σ受体配体可以 代表了一类新的化合物， 剂.

This projects delineates biochemical and pharmacological properties of sigma receptors and ligands. In this fiscal year, we found that a neuroleptic sulpiride can potentiate the NMDA-induced increase in intracellular calcium concentration and that this action of sulpiride is in turn enhanced by sigma ligands. Also, it was found that this action of sulpiride is blocked by protein kinase A inhibitor. The results indicate a relationship between the action of neuroleptics and sigma ligands and suggest that the action of either or both classes of drugs could invlove intracellular calcium signaling and protein hosphorylation. Behaviorally, we found that a synthetic sigma ligand PRE-084, like neurosteroids pregnenolone sulfate and dihydroepiandrosterone, improves learning and memory in mice whose mnemonic capacities were compromized by the icv injection of beta-amyloid peptide 25-35. Further, the action of all three compounds are blocked by progesterone, a neurosteroid which binds sigma receptors. Thus, sigma receptor ligands may represent a new class of compounds for developing antiamnesic agents.