Development of Thiochroman Dioxide Analogues of Benzothiadiazine Dioxides as New Positive Allosteric Modulators of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptors

Abstract

On the basis of the activity of 1,2,4-benzothiadiazine 1,1-dioxides as positive allosteric modulators of AMPA receptors, thiochroman 1,1-dioxides were designed applying the isosteric replacement concept. The new compounds expressed strong modulatory activity on AMPA receptors <i>in vitro</i>, although lower than their corresponding benzothiadiazine analogues. The pharmacokinetic profile of three thiochroman 1,1-dioxides (<b>12a</b>, <b>12b</b>, <b>12e</b>) was examined <i>in vivo</i> after oral administration, showing that these compounds freely cross the blood-brain barrier. Structural analysis was achieved using X-ray crystallography after cocrystallization of the racemic compound <b>12b</b> in complex with the ligand-binding domain of GluA2 (L504Y/N775S). Interestingly, both enantiomers of <b>12b</b> were found to interact with the GluA2 dimer interface, almost identically to its benzothiadiazine analogue, BPAM344 (<b>4</b>). The interactions of the two enantiomers in the cocrystal were further analyzed (mapping Hirshfeld surfaces and 2D fingerprint) and compared to those of <b>4</b>. Taken together, these data explain the lower affinity on AMPA receptors of thiochroman 1,1-dioxides compared to their corresponding 1,2,4-benzothiadiazine 1,1-dioxides.