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

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-benzothiadiazine 1,1-dioxide, ec 50 = 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.