A Blood–Brain Barrier‐Permeable Guanylhydrazone Analogue of the ASIC3 Activator GMQ Inhibits Human Glioblastoma Stem Cell Growth In Vitro

The acid-sensing ion channel 3 (ASIC3) is a neuronal voltage-insensitive Na+ channel located in the peripheral nervous system (PNS) and activated by extracellular H+, that is dysregulated in peripheral neuropathic pain. ASIC3 was found in stem cells of central nervous system (CNS)–located glioblastoma multiforme (GBM CSCs), and its chronic activation kills dysfunctional GBM CSCs without any effect on ASIC3-lacking CNS tissues. We rationally designed and synthesized blood–brain barrier (BBB)–compliant analogues of GMQ, a known guanidyl quinazoline ASIC3 activator; we replaced its guanidine group with a guanyl hydrazone (GH) and carried out scaffold substitutions and other structural variations in 16 GMQ analogues to establish a structure–activity relationship (SAR). Our more potent GH analogue 1a showed specific activity against GBM CSC neurospheres, coupled with a better safety profile on mammalian nontumor cells and a better brain-to-plasma ratio compared with GMQ. Such results provide valuable insights for further structural optimization of heteroaryl GHs as ASIC3 modulators.