Pharmacologic Inhibition of PDE11A for Age-Related Memory Disorders

项目摘要 与抑郁症有关的记忆丧失仍然是一种没有有效治疗方法的疾病。 数据表明，大脑中与记忆相关的特定区域中发现的一种酶， 磷酸二酯酶11A（PDE11A）随着人类年龄的增长而表达增加， 大脑中作为这种酶底物的关键信号分子串联减少， 这导致了PDE11A直接导致这种效应的假设。我们的实验 缺乏PDE11A的小鼠显示，这些动物的行为和繁殖正常， 患有与它们的野生型同窝出生仔相同的年龄相关的记忆丧失。该数据 共同导致了这样的假设，即PDE11A可能是一种有价值的研究靶标， 治疗与年龄有关的记忆丧失 没有已知的有效和选择性的PDE11A抑制剂。许多其他PDE 酶正在研究或已经研究了各种精神病和 神经退行性疾病，表明这个家族可以被小分子靶向。一 使用表达人PDE11A的酵母的新筛选方法鉴定了许多良好的 起点。这些命中中的一些显示出对PDE11A的优异选择性， 优化的潜力，以提供第一种有效的选择性PDE11A抑制剂，其特征在于， 将使我们能够在小鼠模型中研究这些化合物的年龄相关行为， 记忆

Project Summary Age-related loss of memory remains a disease for which there are no effective treatments. Data suggests that an enzyme found in a specific region of the brain associated with memory, phosphodiesterase 11A (PDE11A), is increasingly expressed as humans age, and that levels of key signaling molecules in the brain that are substrates for this enzyme decrease in tandem, leading to the hypothesis that PDE11A is directly responsible for this effect. Our experiments with mice lacking PDE11A revealed that these animals behave and reproduce normally and do not suffer from the same age related loss of memory as their wild type littermates. This data collectively leads to the hypothesis that PDE11A may be a valuable target for study as a means to treat age-related loss of memory. There are no known potent and selective PDE11A inhibitors. A number of other PDE enzymes are under investigation or have been studied for various psychiatric and neurodegenerative diseases, indicating that this family can be targeted by small molecules. A novel screening method using yeast that express human PDE11A identified a number of good starting points. Some of these hits demonstrated excellent selectivity for PDE11A with the potential to be optimized to provide the first potent, selective PDE11A inhibitors with a profile that will allow us to investigate these compounds in mouse models of age-related behavior and memory.