Amongst the ionotropic receptors responding to glutamate appears the AMPA subtype, which mediates fast excitatory transmission in the brain. It is now well established that AMPA receptors are involved in the expression and the maintenance of long-term potentiation, a phenomenon that has been closely linked to learning and memory processes. Hence the AMPA receptors are considered as an attractive target to develop cognitive enhancers.

AMPA agonists were first proposed for this purpose, but were found to cause adverse effects. Positive allosteric modulators acting on AMPA receptors ("AMPA potentiators" or "AMPA PAMs") represent an interesting alternative to agonists, since they are able to only potentiate AMPA signals in the presence of the endogenous neurotransmitter. Experimental and clinical data from the last decade have proven the therapeutic interest of AMPA PAMs as cognitive enhancers. Additional works have recently highlighted their potential value as a novel approach for the management of schizophrenia or depression.

Benzothiadiazine 1,1-dioxides constitute a chemical class currently investigated for the discovery of new AMPA PAMs. Starting from the structure of cyclothiazide (1) and IDRA-21 (2), our team previously synthesized in vitro active 2,3-dihydro-4H- benzothiadiazine 1,1-dioxides from which emerged BPAMPA 50 (3), bearing a short alkyl chain in the 4-position.

This work presents the preparation of novel AMPA PAMs structurally related to BPAMPA50 (3) and focalises on structure-activity relationships deduced from their in vitro activity. Particular attention is paid to the influence of the substituent in the 7-position, although substituents at the 2- and 4-positions of the heterocycle are orientated based on the structure-activity relationships previously established by our team. Biological evaluations are realized in vitro on Xenopus oocytes expressing AMPA receptors.