Inhibition of phoshodiesterase type 2 or type 10 reverses object memory deficits induced by scopolamine or MK-801

Introduction: Phosphodiesterase (PDE) inhibitors improve signaling pathways in brain circuits by increasing intracellular cyclic adenosine monophosphate (cAMP) and/or cyclic guanosine monophosphate (cGMP). In the last decade, the first clinical studies investigating selective PDE inhibitors in Alzheimer's disease (AD) have been initiated, based on their positive effects on cognitive processes and neuroprotection in numerous animal studies. Areas covered: This article reviews the clinical studies investigating the pro-cognitive/neuroprotective effects of PDE inhibitors in patients with AD, as well as in age-associated memory impaired elderly and patients with mild cognitive impairment (MCI), the prodromal stage of AD. PDE inhibitors will also be discussed with respect to adverse effects including safety and tolerability. Expert opinion: The limited available data of clinical studies with PDE inhibitors tested in different populations of AD patients do not allow the drawing of any concrete conclusion yet. Currently, studies with a PDE3 (cilostazol) or PDE9 inhibitor (BI 409,306) are still ongoing in patients with MCI or AD, respectively. Studies with PDE4 inhibitors (HT-0712, roflumilast and BPN14770) in healthy elderly and elderly with age-associated memory impairments indicate that the optimum dose and/or inhibiting the most relevant PDE isoform hold great promise when tested in the appropriate population of patients with MCI or AD eventually. ARTICLE HISTORY

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“…[101][102][103]). Until now no PDE10 inhibitors have been tested in clinical trials of aging and AD.…”

Section: Phosphodiesterase 10mentioning

confidence: 99%

Investigational phosphodiesterase inhibitors in phase I and phase II clinical trials for Alzheimer’s disease

Prickaerts

Heckman

Blokland

2017

Expert Opinion on Investigational Drugs

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133

168

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“…We administered three selective PDE inhibitors: PDE2 inhibitor BAY 60-7550 (IC 50 : 4.7 nM; kindly donated by BAYER AG, Wuppertal, Germany), PDE4 inhibitor rolipram (IC 50 : 1.5 nM; Sigma Aldrich, Zwijndrecht, the Netherlands) and PDE5 inhibitor vardenafil (IC 50 : 0.7 nM; kindly donated by BAYER AG). All three PDE inhibitors have been shown to cross the blood-brain barrier (Krause and Kuhne, 1988;Reneerkens et al, 2012;Reneerkens et al, 2013). The PKA inhibitor Rp-8-Br-cAMPS and PKG inhibitor Rp-8-Br-cGMPS were obtained from Biolog (Bremen, Germany).…”

Section: Drug Administrationmentioning

confidence: 99%

Improved Long-Term Memory via Enhancing cGMP-PKG Signaling Requires cAMP-PKA Signaling

Bollen

Puzzo

Rutten

et al. 2014

Neuropsychopharmacol

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Memory consolidation is defined by the stabilization of a memory trace after acquisition, and consists of numerous molecular cascades that mediate synaptic plasticity. Commonly, a distinction is made between an early and a late consolidation phase, in which early refers to the first hours in which labile synaptic changes occur, whereas late consolidation relates to stable and long-lasting synaptic changes induced by de novo protein synthesis. How these phases are linked at a molecular level is not yet clear. Here we studied the interaction of the cyclic nucleotide-mediated pathways during the different phases of memory consolidation in rodents. In addition, the same pathways were studied in a model of neuronal plasticity, long-term potentiation (LTP). We demonstrated that cGMP/protein kinase G (PKG) signaling mediates early memory consolidation as well as early-phase LTP, whereas cAMP/protein kinase A (PKA) signaling mediates late consolidation and late-phase-like LTP. In addition, we show for the first time that early-phase cGMP/PKG signaling requires late-phase cAMP/PKA-signaling in both LTP and long-term memory formation.

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“…ND7001 was under development by Neuro 3D and advanced into clinical phase I in 2005, showing potent inhibitory activity against PDE2 [14] with IC 50 value of 57 nM. However, according to the reports of Thomson Reuters Pharma, developments of BAY 60-7550 and ND7001 were ceased due to their poor pharmacokinetics performances [15].…”

Section: Introductionmentioning

confidence: 99%

Purin-6-One Derivatives as Phosphodiesterase-2 Inhibitors

Wang

Zhao

Chen

et al. 2016

Journal of Chemistry

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A series of purin-6-one derivatives were synthesized, and their in vitro inhibitory activity against phosphodiesterase-2 (PDE2) was evaluated by using a fluorescence polarization assay. Three compounds, that are, 2j, 2p, and 2q, showed significant inhibitory activity against PDE2 with IC 50 values of 1.73, 0.18, and 3.43 M, respectively. Structure-activity relationship (SAR) analysis was performed to explore the relationship between the chemical structures of these compounds and their inhibitory activity. Compounds 2j, 2p, and 2q were further selected for molecular docking study. The docking results suggested that these ligands bind with hydrophobic pockets of the catalytic active site of PDE2, where a Tyr655 residue was found to be important in binding with compound 2p, the most potent inhibitor identified in this study. Our present study provides useful information for the future design of novel PDE2 inhibitors.

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Inhibition of phoshodiesterase type 2 or type 10 reverses object memory deficits induced by scopolamine or MK-801

Cited by 79 publications

References 62 publications

Investigational phosphodiesterase inhibitors in phase I and phase II clinical trials for Alzheimer’s disease

Investigational phosphodiesterase inhibitors in phase I and phase II clinical trials for Alzheimer’s disease

Improved Long-Term Memory via Enhancing cGMP-PKG Signaling Requires cAMP-PKA Signaling

Purin-6-One Derivatives as Phosphodiesterase-2 Inhibitors

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