7-Phenoxy-Substituted 3,4-Dihydro-2 H -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
2017; American Chemical Society; Volume: 61; Issue: 1 Linguagem: Inglês
10.1021/acs.jmedchem.7b01323
ISSN1520-4804
AutoresEric Goffin, Thomas Drapier, A.P. Larsen, Pierre Geubelle, Christopher P. Ptak, Saara Laulumaa, Karoline Rovinskaja, Julie Gilissen, Pascal De Tullio, Lars Olsen, Karla Frydenvang, Bernard Pirotte, Julien Hanson, Robert E. Oswald, J.S. Kastrup, Pierre Francotte,
Tópico(s)Synthesis and Reactions of Organic Compounds
ResumoWe 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-benzothiadiazine 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.
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