[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
scite shows how a scientific paper has been cited by providing the context of the citation, a classification describing whether it supports, mentions, or contrasts the cited claim, and a label indicating in which section the citation was made.
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