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On the basis of the results obtainedin previous series of AMPApotentiators belonging to 3,4-dihydro-2H-benzo- and3,4-dihydro-2H-pyrido-1,2,4-thiadiazine 1,1-dioxides,the present work focuses on the design of original isosteric 3,4-dihydro-2H-thieno-1,2,4-thiadiazine 1,1-dioxides. Owing to the sulfurposition, three series of compounds were developed and their activityas AMPA potentiators was characterized. In each of the developed series,potent compounds were discovered. After screening the selected activecompounds on a safety in vivo test, 6-chloro-4-ethyl-3,4-dihydro-2H-thieno[2,3-e]-1,2,4-thiadiazine 1,1-dioxide(24) appeared as the most promising compound and wasfurther evaluated. Its effects on long-term potentiation in vivo andon AMPA-mediated noradrenaline release were measured to predict itspotential cognitive enhancing properties. Finally, an object recognitiontest performed in mice revealed that 24was able to significantlyenhance cognition, after oral administration, at doses as low as 0.3mg/kg. This study validates the interest of the isosteric replacementof the benzene or pyridine nuclei by the thiophene nucleus in thering-fused thiadiazine dioxides class of AMPA potentiators. [ABSTRACT FROM AUTHOR]