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 in vitro, although lower than their corresponding benzothiadiazine analogues. The pharmacokinetic profile of three thiochroman 1,1-dioxides (12a, 12b, 12e) was examined in vivo 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 12b in complex with the ligand-binding domain of GluA2 (L504Y/N775S). Interestingly, both enantiomers of 12b were found to interact with the GluA2 dimer interface, almost identically to its benzothiadiazine analogue, BPAM344 (4). The interactions of the two enantiomers in the cocrystal were further analyzed (mapping Hirshfeld surfaces and 2D fingerprint) and compared to those of 4. 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.

Describing auxin solid state intermolecular interactions using contact descriptors, shape property and molecular fingerprint: comparison of pure auxin crystal and auxin-TIR1 co-crystal

“…The Hirshfeld surfaces (HSs) mapped over different properties like di, de, dnorm, shape-index, electron, and deformation density, and the 2D fingerprint plots were generated using CrystalExplorer 17.5 [23] and the data were obtained according to the procedure previously described [24]. The cocrystal structure of auxin with TIR1 (PDB code 2P1Q, resolution of 1.91 Å) retrieved from the protein data bank (PDB) was used in the study [16].…”

Exploring thienothiadiazine dioxides as isosteric analogues of benzo- and pyridothiadiazine dioxides in the search of new AMPA and kainate receptor positive allosteric modulators

“…We have recently focused on developing new AMPAR PAMs belonging to the BTD-type compounds starting from the structure pattern of the orally active AMPAR potentiator IDRA 21 ( 1 , Figure 1) [23–35]. New orally active BTD compounds such as 2 and 3 (Figure 1) were reported to express improved in vitro properties and in vivo efficacy [25, 29].…”

“…More recently, 7-phenoxy-substituted BTDs such as 7 (Figure 1) [33] and dimers such as 8 (Figure 1) [34] have been shown to be particularly potent as AMPAR modulators, potentiating the effect of glutamate on these receptors in the nanomolar range [33,34]. Based on the isosteric replacement concept, thiochroman 1,1-dioxides like 9 , which is the structural analogue of the potent compound 10 , were also found to express a noticeable potentiator activity on the AMPARs [35]. Finally, examples of BTDs bearing an alkyl substituent at the 2- and/or the 3-position(s) were also explored, providing interesting potentiators of the AMPARs [31].…”

“…(1, Figure 1) [23][24][25][26][27][28][29][30][31][32][33][34][35]. New orally active BTD compounds such as 2 and 3 (Figure 1) were reported to express improved in vitro properties and in vivo efficacy [25,29].…”

α-Lipoic Acid Derivatives as Allosteric Modulators for Targeting AMPA-Type Glutamate Receptors’ Gating Modules

“…Controlling AMPAR activity is being investigated as a potential treatment for neurological and psychiatric conditions. Even though there has been an increase in the development of AMPAR positive and negative allosteric modulators (PAMs and NAMs) [ 20 ], they have been found to lack selectivity for distinct brain areas [ 21 , 22 , 23 ]. For example, the NAM perampanel is effective against various seizure types, but its lack of regional specificity leads to side effects such as ataxia and dizziness [ 22 , 24 ].…”