title: 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.
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.
authors: Department of Pharmacy, Section of Medicinal Chemistry, School of Medical and Pharmaceutical Sciences, University of Genoa, Viale Benedetto XV, 3, 16132 Genoa, Italy.
authors: Chiara
authors: C
authors: Brullo
authors: Department of Experimental Medicine, Section of General Pathology, School of Medical and Pharmaceutical Sciences, University of Genoa, Via L.B. Alberti, 2, 16132 Genoa, Italy.
authors: Roberta
authors: R
authors: Ricciarelli
authors: Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNS), Maastricht University, Universiteitssingel 50, 6229 ER, Maastricht, The Netherlands.
authors: Jos
authors: J
authors: Prickaerts
authors: Department of Pathology & Cell Biology, Taub Institute for Research on Alzheimer's Disease and the Aging Brain, Columbia University, New York, NY 10032, USA.
authors: Ottavio
authors: O
authors: Arancio
authors: Department of Pharmacy, Section of Medicinal Chemistry, School of Medical and Pharmaceutical Sciences, University of Genoa, Viale Benedetto XV, 3, 16132 Genoa, Italy.
authors: Matteo
authors: M
authors: Massa
authors: Department of Pharmacy, Section of Medicinal Chemistry, School of Medical and Pharmaceutical Sciences, University of Genoa, Viale Benedetto XV, 3, 16132 Genoa, Italy.
authors: Chiara
authors: C
authors: Rotolo
authors: Department of Pharmacy, Section of Medicinal Chemistry, School of Medical and Pharmaceutical Sciences, University of Genoa, Viale Benedetto XV, 3, 16132 Genoa, Italy.
authors: Alessia
authors: A
authors: Romussi
authors: Department of Pharmacy, Section of Pharmacology and Toxicology, School of Medical and Pharmaceutical Sciences, University of Genoa, Viale Cembrano, 4, 16147 Genoa, Italy.
authors: Claudia
authors: C
authors: Rebosio
authors: Department of Experimental Medicine, Section of General Pathology, School of Medical and Pharmaceutical Sciences, University of Genoa, Via L.B. Alberti, 2, 16132 Genoa, Italy.
authors: Barbara
authors: B
authors: Marengo
authors: Department of Experimental Medicine, Section of General Pathology, School of Medical and Pharmaceutical Sciences, University of Genoa, Via L.B. Alberti, 2, 16132 Genoa, Italy.
authors: Maria Adelaide
authors: MA
authors: Pronzato
authors: Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNS), Maastricht University, Universiteitssingel 50, 6229 ER, Maastricht, The Netherlands.
authors: Britt T J
authors: BTJ
authors: van Hagen
authors: Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience (MHeNS), Maastricht University, Universiteitssingel 50, 6229 ER, Maastricht, The Netherlands.
authors: Nick P
authors: NP
authors: van Goethem
authors: Institute for Biomedical Technologies and National Research Council (ITB-CNR), Via Fratelli Cervi 93, 20090 Segrate, MI, Italy.
authors: Pasqualina
authors: P
authors: D'Ursi
authors: Institute for Biomedical Technologies and National Research Council (ITB-CNR), Via Fratelli Cervi 93, 20090 Segrate, MI, Italy.
authors: Alessandro
authors: A
authors: Orro
authors: Institute for Biomedical Technologies and National Research Council (ITB-CNR), Via Fratelli Cervi 93, 20090 Segrate, MI, Italy.
authors: Luciano
authors: L
authors: Milanesi
authors: Department of Pharmacy, Section of Medicinal Chemistry, School of Medical and Pharmaceutical Sciences, University of Genoa, Viale Benedetto XV, 3, 16132 Genoa, Italy.
authors: Sara
authors: S
authors: Guariento
authors: Department of Pharmacy, Section of Medicinal Chemistry, School of Medical and Pharmaceutical Sciences, University of Genoa, Viale Benedetto XV, 3, 16132 Genoa, Italy.
authors: Elena
authors: E
authors: Cichero
authors: Department of Pharmacy, Section of Medicinal Chemistry, School of Medical and Pharmaceutical Sciences, University of Genoa, Viale Benedetto XV, 3, 16132 Genoa, Italy.
authors: Paola
authors: P
authors: Fossa
authors: Department of Pharmacy, Section of Pharmacology and Toxicology, School of Medical and Pharmaceutical Sciences, University of Genoa, Viale Cembrano, 4, 16147 Genoa, Italy; Center of Excellence for Biomedical Research, University of Genoa, Viale Benedetto XV, 9, 16132 Genoa, Italy.
authors: Ernesto
authors: E
authors: Fedele
authors: Department of Pharmacy, Section of Medicinal Chemistry, School of Medical and Pharmaceutical Sciences, University of Genoa, Viale Benedetto XV, 3, 16132 Genoa, Italy. Electronic address: obruno@unige.it.
authors: Olga
authors: O
authors: Bruno
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D000242:Cyclic AMP / Q000378:metabolism; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4 / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D007097:Imines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D008297:Male; D008568:Memory / Q000187:drug effects*; D051379:Mice; D062105:Molecular Docking Simulation; D056004:Molecular Dynamics Simulation; D009025:Morpholines / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D058988:Phosphodiesterase 4 Inhibitors / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D012601:Scopolamine / Q000494:pharmacology
chemical_list: C570687:GEBR-7b; D007097:Imines; D009025:Morpholines; D058988:Phosphodiesterase 4 Inhibitors; D012601:Scopolamine; D000242:Cyclic AMP; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4
keywords: In silico ADMET properties; Memory behavior test; Molecular dynamics simulation; PDE4D inhibitors; Pharmacokinetic analyses; cAMP enhancers