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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.