By Omar Alijevic, Hassan Hammoud, Anand Vaithia, Viktor Trendafilov, Maud Bollenbach, Martine Schmitt, Frédéric Bihel, and Stephan Kellenberger. In ACS Chemical Neuroscience, 10.1021/acschemneuro.7b00529
The Acid-sensing ion channels (ASICs) are pH sensors of the nervous system, and with this involved in many physiological and pathological processes, such as pain, fear, learning and neurodegeneration after ischemic stroke. ASIC activity is regulated by endogenous and exogenous modulators. 2-Guanidine-4-methylquinazoline (GMQ) is a modulator of ASICs that has recently raised high interest. A drawback of this compound is however that it has a low potency. In the current study we synthesized and functionally tested new derivatives of GMQ. We discovered compounds with diverse properties on ASICs. Several of them lowered the IC50 of channel inhibition by about 20-fold. One subclass of GMQ derivatives, 2-guanidino-quinolines and –pyridines, showed a concentration-dependent biphasic effect that resulted at higher concentrations in ASIC1a and ASIC3 inhibition, while causing at lower concentration a potentiation of ASIC1a, but not ASIC3 currents. In conclusion, we describe a new family of small molecules as ASIC ligands and identify an ASIC subtype-specific potentiation by a subgroup of these compounds.