Identification and structure-function study of positive allosteric modulators of kainate receptors
Mol Pharmacol. 2017-03-30; 91(6): 576-585
DOI: 10.1124/mol.116.107599
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1. Mol Pharmacol. 2017 Jun;91(6):576-585. doi: 10.1124/mol.116.107599. Epub 2017 Mar
30.
Identification and Structure-Function Study of Positive Allosteric Modulators of
Kainate Receptors.
Larsen AP(1), Fièvre S(1), Frydenvang K(1), Francotte P(1), Pirotte B(1), Kastrup
JS(2), Mulle C(2).
Author information:
(1)Biostructural Research, Department of Drug Design and Pharmacology, Faculty of
Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
(A.P.L., K.F., J.S.K.); Interdisciplinary Institute for Neuroscience, University
of Bordeaux, Centre National de la Recherche Scientifique, Unité Mixte de
Recherche 5297, Bordeaux, France (A.P.L., S.F., C.M.); and Department of
Medicinal Chemistry, Center for Interdisciplinary Research on Medicines,
University of Liège, Liège, Belgium (P.F., B.P.).
(2)Biostructural Research, Department of Drug Design and Pharmacology, Faculty of
Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
(A.P.L., K.F., J.S.K.); Interdisciplinary Institute for Neuroscience, University
of Bordeaux, Centre National de la Recherche Scientifique, Unité Mixte de
Recherche 5297, Bordeaux, France (A.P.L., S.F., C.M.); and Department of
Medicinal Chemistry, Center for Interdisciplinary Research on Medicines,
University of Liège, Liège, Belgium (P.F., B.P.)
.
Kainate receptors (KARs) consist of a class of ionotropic glutamate 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 available 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 μM), with an EC50 of 79 μM. 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
concentration of 300 μM with an EC50 value of 159 μM, 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 μM). BPAM344 (100
μM) 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.
Copyright © 2017 by The American Society for Pharmacology and Experimental
Therapeutics.
DOI: 10.1124/mol.116.107599
PMID: 28360094 [Indexed for MEDLINE]