1. Synthesis and Characterization of Novel Mono- and Bis-Guanyl Hydrazones as Potent and Selective ASIC1 Inhibitors Able to Reduce Brain Ischemic Insult
- Author
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Gornati, Davide, Ciccone, Roselia, Vinciguerra, Antonio, Ippati, Stefania, Pannaccione, Anna, Petrozziello, Tiziana, Pizzi, Erika, Hassan, Amal, Colombo, Eleonora, Barbini, Stefano, Milani, Mario, Caccavone, Cecilia, Randazzo, Pietro, Muzio, Luca, Annunziato, Lucio, Menegon, Andrea, Secondo, Agnese, Mastrangelo, Eloise, Pignataro, Giuseppe, and Seneci, Pierfausto
- Abstract
Acid-sensitive ion channels (ASICs) are sodium channels partially permeable to Ca2+ions, listed among putative targets in central nervous system (CNS) diseases in which a pH modification occurs. We targeted novel compounds able to modulate ASIC1 and to reduce the progression of ischemic brain injury. We rationally designed and synthesized several diminazene-inspired diaryl mono- and bis-guanyl hydrazones. A correlation between their predicted docking affinities for the acidic pocket (AcP site) in chicken ASIC1 and their inhibition of homo- and heteromeric hASIC1 channels in HEK-293 cells was found. Their activity on murine ASIC1a currents and their selectivity vs mASIC2a were assessed in engineered CHO-K1 cells, highlighting a limited isoform selectivity. Neuroprotective effects were confirmed in vitro, on primary rat cortical neurons exposed to oxygen-glucose deprivation followed by reoxygenation, and in vivo, in ischemic mice. Early lead 3b, showing a good selectivity for hASIC1 in human neurons, was neuroprotective against focal ischemia induced in mice.
- Published
- 2021
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