4-Chlorophenylguanidine is an ASIC3 agonist and positive allosteric modulator

Abstract

Acid-sensing ion channels (ASICs) are proton-sensitive sodium channels that open in response to lowered extracellular pH and are expressed in the central and peripheral nervous systems. The ASIC3 subtype is found primarily in the periphery where the channel mediates pain signals caused by ischemia and inflammation. Here, we provide identify 4-chlorophenylguanidine (4-CPG) as an ASIC3 positive allosteric modulator and newest member of the growing group of guanidine modulators of ASICs. Furthermore, the 4-CPG reversed the effects of ASIC3 desensitization. The molecule 4-CPG offers a novel chemical backbone for the design of new ASIC3 ligands to study ASIC3 in vivo.

Acid-sensing ion channel 3: An analgesic target

“…GMQ has an EC 50 of 680 µM (in rASIC3 at pH 7.4), compounds with related structures guanabenz and sephin1 having an EC 50 for activation at neutral pH of 67.5 µM and 1220 µM, respectively; in addition, GMQ and guanabenz enhanced transient and sustained phases of acid-activation of ASIC3 [ 192 ]. Another guanidine-based compound is 4-chlorophenylguanidine (4-CPG, Figure 7b ), which has been shown to increase the ASIC3 half-maximal pH activation from 6.79 to 7.12; but only at a very high concentration of 1 mM [ 193 ]. Lastly, a structure similar to GMQ, is chloroquine (CQ, Figure 7c ), which has also been shown to increase only the sustained rASIC3 currents at pH 7 (EC 50 435.2 µM), an effect largely abolished if Glu79 is mutated and completely abolished if Glu423 is mutated; excitingly, CQ-induced itching behavior in mice was ablated by the ASIC3 blocker APETx2 [ 194 ].…”