Synthesis and Characterization of Novel Mono- and Bis-Guanyl Hydrazones as Potent and Selective ASIC1 Inhibitors Able to Reduce Brain Ischemic Insult

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.