Design and synthesis of key intermediates giving access to potentiators for the kainate subtype glutamate receptors.

Abstract

Based on the major role played by glutamate in our brain, the glutamatergic receptors constitute interesting targets to develop therapeutic drugs. Amongst all the pharmacological classes that have been investigated so far stand the AMPA receptor (AMPAR) positive allosteric modulators (AMPARpams). For the last two decades, our laboratory has designed more than five hundred original 1,2,4-benzothiadiazine 1,1-dioxides and isosteres related to IDRA-21 acting as AMPARpams. Amongst these potentiators, stands BPAM344. Recent studies have led to the characterization of the crystallographic structure of the subunits composing kainic acid receptors (KArs) and more particularly their allosteric pocket. Thanks to the discovery of the binding mode of BPAM344 within this site, the design of selective positive allosteric for KArs seemed possible. Based on the preliminary results obtained with the first compounds, new series of benzothiadiazines dioxides have been imagined. The present work describes the obtention of a first key intermediate that should give access to a new set of potentiators, selective for GluK1-3 or GluK4-5 subunits KARs