New substituted aryl esters and aryl amides of 3,4-dihydro-2H-1,2,4- benzothiadiazine 1,1-dioxides as positive allosteric modulators of AMPA receptors

AMPA receptor potentiators belonging to 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides have been found to be of great interest as cognitive enhancers. Previous structure–activity relationships have demonstrated the importance for activity of the nature of the substituent at the 7-position of the heterocycle. This work aims to explore the impact on AMPA potentiation of the introduction of different aryl and aralkyl ester or aryl amide groups at the 7-position. The new synthesized compounds were evaluated as AMPA receptor potentiators by examining their effect on rat brain primary cell cultures on AMPA-evoked membrane depolarisation using fluorescent membrane potential dyes and on imaging-based plate reader. The most potent compound of this series was 2-methylphenyl 4-methyl- 3,4-dihydro-2H-1,2,4-benzothiadiazine-7-carboxylate 1,1-dioxide 16c which provoked a strong potentiation of AMPA current with a potency close to that reported for the best reference compounds of the benzothiadiazine class (i.e cyclothiazide). This work also revealed that only the ortho-substitution of the phenyl group of 1,2,4-benzothiadiazine-7-carboxylate esters provided potent AMPA receptor potentiators opening the way to further chemical exploration.