Synthesis of 3,4-dihydro-2<i>H</i>-1,2-benzothiazine-3-carboxylic acid 1,1-dioxides and their evaluation as ligands for NMDA receptor glycine binding site

<p>A series of 2-substituted 3,4-dihydro-2<i>H</i>-1,2-benzothiazine-3-carboxylic acid 1,1-dioxides were synthesized and evaluated for their affinity to the glycine binding site of the <i>N</i>-methyl-d-aspartate (NMDA) receptor. The binding affinity was determined by the displacement of radioligand [<sup>3</sup>H]MDL-105,519 from rat cortical membrane preparations. The most attractive structures in the search for prospective NMDA receptor ligands were identified to be 2-arylcarbonylmethyl substituted 3,4-dihydro-2<i>H</i>-1,2-benzothiazine-3-carboxylic acid 1,1-dioxides. It has been demonstrated for the first time that the replacement of NH group in the ligand by <i>sp</i><sup>3</sup> CH<sub>2</sub> is tolerated. This finding may pave the way for previously unexplored approaches for designing new ligands of the NMDA receptor.</p>