Identification of small molecule inhibitors of amyloid β-induced neuronal apoptosis acting through the imidazoline I₂ receptor

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 I₂ 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 I₂ receptor emerges as a new mechanism of action to inhibit tPA-induced signaling in neurons for the treatment of AD and other neurodegenerative diseases.