The selective phosphodiesterase 9 (PDE9) inhibitor PF-04447943 (6-[(3S,4S)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one) enhances synaptic plasticity and cognitive function in rodents
The selective phosphodiesterase 9 (PDE9) inhibitor PF-04447943 (6-[(3S,4S)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidin-3-yl]-1-(tetrahydro-2H-pyran-4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one) enhances synaptic plasticity and cognitive function in rodents
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DOI：
10.1016/j.neuropharm.2011.05.009
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发表时间：
2011-09-01
影响因子：
4.7
通讯作者：
Parmentier-Batteur, S.
中科院分区：
文献类型：
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作者：
Hutson, P. H.;Finger, E. N.;Parmentier-Batteur, S.
据报道，抑制磷酸二酯酶 9 (PDE9) 可增强啮齿动物的认知功能，并可能代表一种改善阿尔茨海默病认知功能障碍的潜在新方法。 PF-04447943，最近描述的一种 PDE9 抑制剂 (6-[(3S,4S)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidn-3-yl]-1-(tetraHydro-2H-pyran4-yl)-1,5-diHydro-4H-pyrazolo[3,4-d]pyrimidin-4-one) 被发现具有高亲和力（Ki对于人、恒河猴和大鼠重组 PDE9 分别为 2.8、4.5 和 18 nM），与 PDEs1-8 和 10-11 相比，PDE9 具有高选择性。 PF-04447943 在低 (30-100 nM) 但不高 (300-1000 nM) 浓度下显着增加培养的海马神经元中的神经突生长和突触形成（如突触蛋白 1 表达增加所示）。 PF-04447943 显着促进了由浓度为 100 nM 的弱破伤风刺激引起的海马切片 LTP，但未能影响对 30 或 300 nM 弱破伤风的反应，或由 theta 爆发刺激产生的 LTP。 PF-04447943 (1-30 mg/kg p.o.) 的全身给药在给药后 30 分钟剂量依赖性地增加了脑脊液中的 cGMP，表明大鼠 CNS 中的目标参与。 PF-04447943（口服 1-3 mg/kg）显着改善了三种啮齿动物认知试验（自然遗忘的小鼠 Y 迷宫空间识别记忆模型、自然遗忘的小鼠社会识别记忆模型和东莨菪碱缺陷的大鼠新物体识别）的认知表现。当以 3 mg/kg 口服剂量给药时，PF-04447943 显着增加了大鼠海马膜中磷酸化但不总的 GluR1 表达，从而提高了新物体识别的性能。总的来说，这些数据表明 PF-04447943 是一种有效的、选择性的脑渗透性 PDE9 抑制剂，可在大鼠和小鼠的各种认知模型中增加海马突触可塑性指标并改善认知功能。 PF-04447943 的结果与之前发表的使用结构多样的 PDE9 抑制剂 BAY73-6199 的结果一致，并进一步支持这样的观点：PDE9 抑制可能代表了一种姑息治疗认知功能障碍的新方法。 (C) 2011 年，爱思唯尔有限公司出版。
Inhibition of phosphodiesterase 9 (PDE9) has been reported to enhance rodent cognitive function and may represent a potential novel approach to improving cognitive dysfunction in Alzheimer's disease. PF-04447943, (6-[(3S,4S)-4-methyl-1-(pyrimidin-2-ylmethyl)pyrrolidn-3-yl]-1-(tetrahydro-2H-pyran4-yl)-1,5-dihydro-4H-pyrazolo[3,4-d]pyrimidin-4-one), a recently described PDE9 inhibitor, was found to have high affinity (Ki of 2.8, 4.5 and 18 nM) for human, rhesus and rat recombinant PDE9 respectively and high selectivity for PDE9 versus PDEs1-8 and 10-11. PF-04447943 significantly increased neurite outgrowth and synapse formation (as indicated by increased synapsin 1 expression) in cultured hippocampal neurons at low (30-100 nM) but not high (300-1000 nM) concentrations. PF-04447943 significantly facilitated hippocampal slice LTP evoked by a weak tetanic stimulus at a concentration of 100 nM but failed to affect response to the weak tetanus at either 30 or 300 nM, or the LTP produced by a theta burst stimulus. Systemic administration of PF-04447943 (1-30 mg/kg p.o.) dose-dependently increased cGMP in the cerebrospinal fluid 30 min after administration indicating target engagement in the CNS of rats. PF-04447943 (1-3 mg/kg p.o.) significantly improved cognitive performance in three rodent cognition assays (mouse Y maze spatial recognition memory model of natural forgetting, mouse social recognition memory model of natural forgetting and rat novel object recognition with a scopolamine deficit). When administered at a dose of 3 mg/kg p.o., which improved performance in novel object recognition, PF-04447943 significantly increased phosphorylated but not total GluR1 expression in rat hippocampal membranes. Collectively these data indicate that PF-04447943 is a potent, selective brain penetrant PDE9 inhibitor that increased indicators of hippocampal synaptic plasticity and improved cognitive function in a variety of cognition models in both rats and mice. Results with PF-04447943 are consistent with previously published findings using a structurally diverse PDE9 inhibitor, BAY73-6199, and further support the suggestion that PDE9 inhibition may represent a novel approach to the palliative remediation of cognitive dysfunction. (C) 2011 Published by Elsevier Ltd.