Article (Scientific journals)
7‐Phenoxy-Substituted 3,4-Dihydro‐2H‐1,2,4-benzothiadiazine 1,1- Dioxides as Positive Allosteric Modulators of α‐Amino-3-hydroxy-5- methyl-4-isoxazolepropionic Acid (AMPA) Receptors with Nanomolar Potency
Goffin, Eric; Drapier, Thomas; Probst Larsen, Anja et al.
2018In Journal of Medicinal Chemistry, 61, p. 251-264
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Abstract :
[en] We report here the synthesis of 7-phenoxy- substituted 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides and their evaluation as AMPA receptor positive allosteric modulators (AMPApams). The impact of substitution on the phenoxy ring and on the nitrogen atom at the 4-position was examined. At GluA2(Q) expressed in HEK293 cells (calcium flux experiment), the most potent compound was 11m (4- cyclopropyl-7-(3-methoxyphenoxy)-3,4-dihydro-2H-1,2,4-ben- zothiadiazine 1,1-dioxide, EC50 = 2.0 nM). The Hill coefficient in the screening and the shape of the dimerization curve in small-angle X-ray scattering (SAXS) experiments using isolated GluA2 ligand-binding domain (GluA2-LBD) are consistent with binding of one molecule of 11m per dimer interface, contrary to most benzothiadiazine dioxides developed to date. This observation was confirmed by the X-ray structure of 11m bound to GluA2-LBD and by NMR. This is the first benzothiadiazine dioxide AMPApam to reach the nanomolar range.
Disciplines :
Pharmacy, pharmacology & toxicology
Author, co-author :
Goffin, Eric  ;  Université de Liège - ULiège > GIGA-Research
Drapier, Thomas  ;  Université de Liège - ULiège > Département de pharmacie > Chimie pharmaceutique
Probst Larsen, Anja
Geubelle, Pierre ;  Université de Liège - ULiège > Département de pharmacie > Chimie pharmaceutique
Ptak, Christopher P.
Laulumaa, Saara
Rovinskaja, Karoline
Gilissen, Julie
De Tullio, Pascal ;  Université de Liège - ULiège > Département de pharmacie > Chimie pharmaceutique
Olsen, Lars
Frydenvang, Karla
Pirotte, Bernard ;  Université de Liège - ULiège > Unités de recherche interfacultaires > Centre Interdisciplinaire de Recherche sur le Médicament (CIRM)
Hanson, Julien  ;  Université de Liège - ULiège > Département de pharmacie > Chimie pharmaceutique
Oswald, Robert E.
Sandholm Kastrup, Jette
Francotte, Pierre  ;  Université de Liège - ULiège > Département de pharmacie > Chimie pharmaceutique
More authors (6 more) Less
 These authors have contributed equally to this work.
Language :
English
Title :
7‐Phenoxy-Substituted 3,4-Dihydro‐2H‐1,2,4-benzothiadiazine 1,1- Dioxides as Positive Allosteric Modulators of α‐Amino-3-hydroxy-5- methyl-4-isoxazolepropionic Acid (AMPA) Receptors with Nanomolar Potency
Publication date :
2018
Journal title :
Journal of Medicinal Chemistry
ISSN :
0022-2623
eISSN :
1520-4804
Publisher :
American Chemical Society, United States - District of Columbia
Volume :
61
Pages :
251-264
Peer reviewed :
Peer Reviewed verified by ORBi
Available on ORBi :
since 14 February 2018

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