Identification and Structure-Function Study of Positive Allosteric Modulators of Kainate Receptors

[en] Kainate receptors (KARs) consist of a class of ionotropic gluta- mate receptors, which exert diverse pre- and postsynaptic functions through complex signaling regulating the activity of neural circuits. Whereas numerous small-molecule positive allosteric modulators of the ligand-binding domain of (S)-2- amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propanoic acid (AMPA) receptors have been reported, no such ligands are avail- able for KARs. In this study, we investigated the ability of three benzothiadiazine-based modulators to potentiate glutamate-evoked currents at recombinantly expressed KARs. 4-cyclopropyl-7-fluoro-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1- dioxide (BPAM344) potentiated glutamate-evoked currents of GluK2a 21-fold at the highest concentration tested (200 mM), with an EC50 of 79 mM. BPAM344 markedly decreased desensitization kinetics (from 5.5 to 775 ms), whereas it only had a minor effect on deactivation kinetics. 4-cyclopropyl-7-hydroxy-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide (BPAM521) potentiated the recorded peak current amplitude of GluK2a 12-fold at a concen- tration of 300 mM with an EC50 value of 159 mM, whereas no potentiation of the glutamate-evoked response was observed for 7-chloro-4-(2-fluoroethyl)-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide (BPAM121) at the highest concentration of modulator tested (300 mM). BPAM344 (100 mM) also potentiated the peak current amplitude of KAR subunits GluK3a (59-fold), GluK2a (15- fold), GluK1b (5-fold), as well as the AMPA receptor subunit GluA1i (5-fold). X-ray structures of the three modulators in the GluK1 ligand-binding domain were determined, locating two modulator- binding sites at the GluK1 dimer interface. In conclusion, this study may enable the design of new positive allosteric modulators selective for KARs, which will be of great interest for further investigation of the function of KARs in vivo and may prove useful for pharmacologically controlling the activity of neuronal networks.

Research center :

CIRM - Centre Interdisciplinaire de Recherche sur le Médicament - ULiège

Disciplines :

Pharmacy, pharmacology & toxicology

Author, co-author :

Larsen, Anja Probst

Fièvre, Sabine

Frydenvang, Karla

Francotte, Pierre ; Université de Liège > Département de pharmacie > Chimie pharmaceutique

Pirotte, Bernard ; Université de Liège > Département de pharmacie > Chimie pharmaceutique

Kastrup, Jette Sandholm

Mulle, Christophe

Language :

English

Title :

Identification and Structure-Function Study of Positive Allosteric Modulators of Kainate Receptors

Publication date :

June 2017

Journal title :

Molecular Pharmacology

ISSN :

0026-895X

eISSN :

1521-0111

Publisher :

American Society for Pharmacology and Experimental Therapeutics, Bethesda, United States - Maryland

Volume :

Pages :

576-585

Peer reviewed :

Peer Reviewed verified by ORBi

Available on ORBi :

since 23 June 2017

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