Pharmacological modulation of phosphodiesterase-7 as a novel strategy for neurodegenerative disorders

Khan, Heena; Tiwari, Chanchal; Grewal, Amarjot Kaur; Singh, Thakur Gurjeet; Chauhan, Simran; Batiha, Gaber El‐Saber

doi:10.1007/s10787-022-01072-1

Cited by 5 publications

(1 citation statement)

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“…11 PDE5 is among the most studied families in the brain, 12,13 but very recent reports are also supporting the role of PDE1 and PDE7 inhibitors in Alzheimer's disease (AD) and neurodegeneration. 14,15 More in general, brain bioavailable PDE inhibitors activating cGMP signaling are being investigated as potential therapeutic strategies against AD. 11,16 PDE9 is endowed with high affinity for cGMP (K m = 70 nM) and the highest selectivity over cAMP (K m = 230 μM).…”

Section: ■ Introductionmentioning

confidence: 99%

Virtual Screening-Accelerated Discovery of a Phosphodiesterase 9 Inhibitor with Neuroprotective Effects in the Kainate Toxicity In Vitro Model

Landucci,

Ribaudo,

Anyanwu

et al. 2023

ACS Chem. Neurosci.

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In the central nervous system, some specific phosphodiesterase (PDE) isoforms modulate pathways involved in neuronal plasticity. Accumulating evidence suggests that PDE9 may be a promising therapeutic target for neurodegenerative diseases. In the current study, computational techniques were used to identify a nature-inspired PDE9 inhibitor bearing the scaffold of an isoflavone, starting from a database of synthetic small molecules using a ligand-based approach. Furthermore, docking studies supported by molecular dynamics investigations allowed us to evaluate the features of the ligand−target complex. In vitro assays confirmed the computational results, showing that the selected compound inhibits the enzyme in the nanomolar range. Additionally, we evaluated the expression of gene and protein levels of PDE9 in organotypic hippocampal slices, observing an increase following exposure to kainate (KA). Importantly, the PDE9 inhibitor reduced CA3 damage induced by KA in a dose-dependent manner in organotypic hippocampal slices. Taken together, these observations strongly support the potential of the identified nature-inspired PDE9 inhibitor and suggest that such a molecule could represent a promising lead compound to develop novel therapeutic tools against neurological diseases..

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