Inhibitors of phosphodiesterase-4 (PDE4) have beneficial effects on memory in preclinical and clinical studies. Development of these drugs has stalled due to dose-limiting side effects of nausea and emesis. While use of subtype-selective inhibitors (i.e., for PDE4A, B, or D) could overcome this issue, conservation of the catalytic region, to which classical inhibitors bind, limits this approach. The present study examined the effects of BPN14770, an allosteric inhibitor of PDE4D, which binds to a primate-specific, N-terminal region. In mice engineered to express PDE4D with this primate-specific sequence, BPN14770 was 100-fold more potent for improving memory than in wild-type mice; meanwhile, it exhibited low potency in a mouse surrogate model for emesis. BPN14770 also antagonized the amnesic effects of scopolamine, increased cAMP signaling in brain, and increased BDNF and markers of neuronal plasticity associated with memory. These data establish a relationship between PDE4D target engagement and effects on memory for BPN14770 and suggest clinical potential for PDE4D-selective inhibitors.

中文翻译：

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磷酸二酯酶-4D的变构抑制剂BPN14770在野生型和人源化小鼠中的记忆增强作用。

磷酸二酯酶4（PDE4）抑制剂在临床前和临床研究中对记忆具有有益作用。由于恶心和呕吐的剂量限制性副作用，这些药物的开发已经停止。尽管使用亚型选择性抑制剂（即用于PDE4A，B或D）可以克服此问题，但经典抑制剂所结合的催化区域的保守性限制了该方法。本研究检查了BPN14770的作用，BPN14770是一种PDE4D的变构抑制剂，与灵长类动物特定的N末端区域结合。在工程改造中以这种灵长类特异性序列表达PDE4D的小鼠中，BPN14770的记忆力比野生型小鼠高100倍。同时，它在呕吐的小鼠替代模型中显示出低效。BPN14770还拮抗了东pol碱的记忆删除效果，增加大脑中的cAMP信号传导，并增加与记忆有关的BDNF和神经元可塑性标记。这些数据建立了BDE14770的PDE4D靶标参与与记忆效应之间的关系，并暗示了PDE4D选择性抑制剂的临床潜力。