دورية أكاديمية
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.
| العنوان: | 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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| المؤلفون: | Hutson PH; Merck & Co., Inc., Department of Neuroscience, West Point, PA 19486, USA. Peter_Hutson@merck.com, Finger EN, Magliaro BC, Smith SM, Converso A, Sanderson PE, Mullins D, Hyde LA, Eschle BK, Turnbull Z, Sloan H, Guzzi M, Zhang X, Wang A, Rindgen D, Mazzola R, Vivian JA, Eddins D, Uslaner JM, Bednar R, Gambone C, Le-Mair W, Marino MJ, Sachs N, Xu G, Parmentier-Batteur S |
| المصدر: | Neuropharmacology [Neuropharmacology] 2011 Sep; Vol. 61 (4), pp. 665-76. Date of Electronic Publication: 2011 May 19. |
| نوع المنشور: | Comparative Study; Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Pergamon Press Country of Publication: England NLM ID: 0236217 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1873-7064 (Electronic) Linking ISSN: 00283908 NLM ISO Abbreviation: Neuropharmacology Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Oxford : Pergamon Press Original Publication: Oxford, New York, Pergamon. |
| مواضيع طبية MeSH: | 3',5'-Cyclic-AMP Phosphodiesterases/*antagonists & inhibitors , Cognition/*drug effects , Neuronal Plasticity/*drug effects , Phosphodiesterase Inhibitors/*pharmacology , Pyrazoles/*pharmacology , Pyrimidinones/*pharmacology , Synapses/*drug effects , Synapses/*enzymology, 3',5'-Cyclic-AMP Phosphodiesterases/metabolism ; Animals ; CHO Cells ; Cognition/physiology ; Cricetinae ; Cricetulus ; Dose-Response Relationship, Drug ; Female ; HEK293 Cells ; Hippocampus/drug effects ; Hippocampus/enzymology ; Humans ; Macaca mulatta ; Male ; Mice ; Mice, Inbred C57BL ; Mice, Inbred ICR ; Neuronal Plasticity/physiology ; Phosphodiesterase Inhibitors/metabolism ; Pyrazoles/metabolism ; Pyrimidinones/metabolism ; Rats ; Rats, Sprague-Dawley ; Rats, Wistar |
| مستخلص: | 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)pyrrolidin-3-yl]-1-(tetrahydro-2H-pyran-4-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. (Copyright © 2011. Published by Elsevier Ltd.) |
| المشرفين على المادة: | 0 (6-(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) 0 (Phosphodiesterase Inhibitors) 0 (Pyrazoles) 0 (Pyrimidinones) EC 3.1.4.17 (3',5'-Cyclic-AMP Phosphodiesterases) EC 3.1.4.17 (PDE9A protein, human) |
| تواريخ الأحداث: | Date Created: 20110531 Date Completed: 20120525 Latest Revision: 20110705 |
| رمز التحديث: | 20240628 |
| DOI: | 10.1016/j.neuropharm.2011.05.009 |
| PMID: | 21619887 |
| قاعدة البيانات: | MEDLINE |
Full Text Finder | تدمد: | 1873-7064 |
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| DOI: | 10.1016/j.neuropharm.2011.05.009 |