1. Identification of Small Molecule Inhibitors of Amyloid β-Induced Neuronal Apoptosis Acting through the Imidazoline I2 Receptor
- Author
-
Marisol Montolio, Pilar Navarro, Jordi Mestres, Elisabet Gregori-Puigjané, and David Pineda
- Subjects
MAPK/ERK pathway ,Imidazoline receptor ,Apoptosis ,Enzyme-Linked Immunosorbent Assay ,Pharmacology ,Hippocampus ,Receptors, N-Methyl-D-Aspartate ,Neuroprotection ,Mice ,Structure-Activity Relationship ,Alzheimer Disease ,Drug Discovery ,In Situ Nick-End Labeling ,medicine ,Animals ,Extracellular Signal-Regulated MAP Kinases ,Receptor ,Monoamine Oxidase ,Cells, Cultured ,Neurons ,Amyloid beta-Peptides ,Molecular Structure ,Chemistry ,Memantine ,Embryo, Mammalian ,Neuroprotective Agents ,Mechanism of action ,Acetylcholinesterase ,Molecular Medicine ,Imidazoline Receptors ,Monoamine oxidase B ,medicine.symptom ,Signal transduction ,Signal Transduction ,medicine.drug - 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.
- Published
- 2012