title: Identification of small molecule inhibitors of amyloid β-induced neuronal apoptosis acting through the imidazoline I(2) receptor.
abstract: Aberrant activation of signaling pathways plays a pivotal role in central nervous system disorders, such as Alzheimer's disease (AD). Using a combination of virtual screening and experimental testing, novel small molecule inhibitors of tPA-mediated extracellular signal-regulated kinase (Erk)1/2 activation were identified that provide higher levels of neuroprotection from Aβ-induced apoptosis than Memantine, the most recently FDA-approved drug for AD treatment. Subsequent target deconvolution efforts revealed that they all share low micromolar affinity for the imidazoline I(2) receptor, while being devoid of any significant affinity to a list of AD-relevant targets, including the N-methyl-d-aspartate receptor (NMDAR), acetylcholinesterase (AChE), and monoamine oxidase B (MAO-B). Targeting the imidazoline I(2) receptor emerges as a new mechanism of action to inhibit tPA-induced signaling in neurons for the treatment of AD and other neurodegenerative diseases.
authors.affiliation: Cancer Research Program, IMIM-Hospital del Mar Research Institute and University Pompeu Fabra, Parc de Recerca Biomèdica (PRBB), Doctor Aiguader 88, 08003 Barcelona, Catalonia, Spain.
authors.forename: Marisol
authors.initials: M
authors.lastname: Montolio
authors.forename: Elisabet
authors.initials: E
authors.lastname: Gregori-Puigjané
authors.forename: David
authors.initials: D
authors.lastname: Pineda
authors.forename: Jordi
authors.initials: J
authors.lastname: Mestres
authors.forename: Pilar
authors.initials: P
authors.lastname: Navarro
mesh_terms: D000110:Acetylcholinesterase / Q000378:metabolism; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000473:pathology; D016229:Amyloid beta-Peptides / Q000633:toxicity*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D004622:Embryo, Mammalian / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004797:Enzyme-Linked Immunosorbent Assay; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006624:Hippocampus / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D054755:Imidazoline Receptors / Q000378:metabolism*; D020287:In Situ Nick-End Labeling; D051379:Mice; D015394:Molecular Structure; D008995:Monoamine Oxidase / Q000378:metabolism; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D018696:Neuroprotective Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D016229:Amyloid beta-Peptides; D054755:Imidazoline Receptors; D018696:Neuroprotective Agents; D016194:Receptors, N-Methyl-D-Aspartate; C487767:imidazoline receptor 2; D008995:Monoamine Oxidase; D048049:Extracellular Signal-Regulated MAP Kinases; D000110:Acetylcholinesterase