1 research outputs found
Heteroarylguanidines as Allosteric Modulators of ASIC1a and ASIC3 Channels
Acid-sensing ion
channels (ASICs) are neuronal Na<sup>+</sup>-selective
ion channels that open in response to extracellular acidification.
They are involved in pain, fear, learning, and neurodegeneration after
ischemic stroke. 2-Guanidine-4-methylquinazoline (GMQ) was recently
discovered as the first nonproton activator of ASIC3. GMQ is of interest
as a gating modifier and pore blocker of ASICs. It has however a low
potency, and exerts opposite effects on ASIC1a and ASIC3. To further
explore the molecular mechanisms of GMQ action, we have used the guanidinium
moiety of GMQ as a scaffold and tested the effects of different GMQ
derivatives on the ASIC pH dependence and maximal current. We report
that GMQ derivatives containing quinazoline and quinoline induced,
as GMQ, an alkaline shift of the pH dependence of activation in ASIC3
and an acidic shift in ASIC1a. Another group of 2-guanidinopyridines
shifted the pH dependence of both ASIC1a and ASIC3 to more acidic
values. Several compounds induced an alkaline shift of the pH dependence
of ASIC1a/2a and ASIC2a/3 heteromers. Compared to GMQ, guanidinopyridines
showed a 20-fold decrease in the IC<sub>50</sub> for ASIC1a and ASIC3
current inhibition at pH 5. Strikingly, 2-guanidino-quinolines and
-pyridines showed a concentration-dependent biphasic effect that resulted
at higher concentrations in ASIC1a and ASIC3 inhibition (IC<sub>50</sub> > 100 μM), while causing at lower concentration a potentiation
of ASIC1a, but not ASIC3 currents (EC<sub>50</sub> ≈ 10 μM).
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