Heteroarylguanidines as Allosteric Modulators of ASIC1a and ASIC3 Channels.

Détails

Ressource 1Télécharger: Alijevic_ACSChemNeurosci_POST.pdf (2012.97 [Ko])
Etat: Public
Version: de l'auteur
ID Serval
serval:BIB_11B0CE680BFE
Type
Article: article d'un périodique ou d'un magazine.
Collection
Publications
Titre
Heteroarylguanidines as Allosteric Modulators of ASIC1a and ASIC3 Channels.
Périodique
ACS chemical neuroscience
Auteur(s)
Alijevic O., Hammoud H., Vaithia A., Trendafilov V., Bollenbach M., Schmitt M., Bihel F., Kellenberger S.
ISSN
1948-7193 (Electronic)
ISSN-L
1948-7193
Statut éditorial
Publié
Date de publication
20/06/2018
Peer-reviewed
Oui
Volume
9
Numéro
6
Pages
1357-1365
Langue
anglais
Notes
Publication types: Journal Article ; Research Support, Non-U.S. Gov't
Publication Status: ppublish
Résumé
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.
Mots-clé
Acid Sensing Ion Channels/drug effects, Acid Sensing Ion Channels/metabolism, Animals, CHO Cells, Cricetinae, Cricetulus/metabolism, Guanidines/pharmacology, Hydrogen-Ion Concentration/drug effects, Ion Channel Gating/drug effects, Ligands, Neurons/drug effects, Quinazolines/pharmacology, Acid-sensing ion channel, channel regulation, compound testing, structure−activity relationship
Pubmed
Web of science
Création de la notice
11/05/2018 15:25
Dernière modification de la notice
21/08/2019 6:08
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