1. New insights into selective PDE4D inhibitors: 3-(Cyclopentyloxy)-4-methoxybenzaldehyde O-(2-(2,6-dimethylmorpholino)-2-oxoethyl) oxime (GEBR-7b) structural development and promising activities to restore memory impairment
- Author
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Brullo, Chiara, Ricciarelli, Roberta, Prickaerts, Jos, Arancio, Ottavio, Massa, Matteo, Rotolo, Chiara, Romussi, Alessia, Rebosio, Claudia, Marengo, Barbara, Pronzato, Maria Adelaide, van Hagen, Britt T J, van Goethem, Nick P., D'Ursi, Pasqualina, Orro, Alessandro, Milanesi, Luciano, Guariento, Sara, Cichero, Elena, Fossa, Paola, Fedele, Ernesto, Bruno, Olga, RS: MHeNs - R3 - Neuroscience, Psychiatrie & Neuropsychologie, and Promovendi MHN
- Subjects
0301 basic medicine ,Male ,Molecular model ,cAMP enhancers ,Morpholines ,Scopolamine ,Pharmacokinetic analyses ,Hippocampus ,Pharmacology ,Memory behavior test ,Molecular Dynamics Simulation ,CREB ,Rats, Sprague-Dawley ,In silico ADMET properties ,Molecular dynamics simulation ,PDE4D inhibitors ,Drug Discovery3003 Pharmaceutical Science ,Organic Chemistry ,03 medical and health sciences ,Mice ,0302 clinical medicine ,Pharmacoldnetic analyses ,Memory ,Catalytic Domain ,Cell Line, Tumor ,Drug Discovery ,Cyclic AMP ,Memory impairment ,Animals ,Humans ,biology ,Behavior, Animal ,Chemistry ,Phosphodiesterase ,General Medicine ,Cyclic Nucleotide Phosphodiesterases, Type 4 ,Rats ,Molecular Docking Simulation ,030104 developmental biology ,Synaptic plasticity ,biology.protein ,Phosphorylation ,Imines ,Phosphodiesterase 4 Inhibitors ,030217 neurology & neurosurgery ,Intracellular - Abstract
Phosphodiesterase type 4D (PDE4D) has been indicated as a promising target for treating neurodegenerative pathologies such as Alzheimer's Disease (AD). By preventing cAMP hydrolysis, PDE4 inhibitors (PDE4Is) increase the cAMP response element-binding protein (CREB) phosphorylation, synaptic plasticity and long-term memory formation. Pharmacological and behavioral studies on our hit GEBR-7b demonstrated that selective PDE4DIs could improve memory without causing emesis and sedation. The hit development led to new molecule series, herein reported, characterized by a catechol structure bonded to five member heterocycles. Molecular modeling studies highlighted the pivotal role of a polar alkyl chain in conferring selective enzyme interaction. Compound 8a showed PDE4D3 selective inhibition and was able to increase intracellular cAMP levels in neuronal cells, as well as in the hippocampus of freely moving rats. Furthermore, 8a was able to readily cross the blood-brain barrier and enhanced memory performance in mice without causing any emetic-like behavior. These data support the view that PDE4D is an adequate molecular target to restore memory deficits in different neuropathologies, including AD, and also indicate compound 8a as a promising candidate for further preclinical development.
- Published
- 2016