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

Abstract

A series of 2-substituted 3,4-dihydro-2H-1,2-benzothiazine-3-carboxylic acid 1,1-dioxides were synthesized and evaluated for their affinity to the glycine binding site of the N-methyl-d-aspartate (NMDA) receptor. The binding affinity was determined by the displacement of radioligand [³H]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-2H-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 sp³ CH₂ is tolerated. This finding may pave the way for previously unexplored approaches for designing new ligands of the NMDA receptor.

• 3
• 4-Dihydro-2H-1
• 2-benzothiazine-3-carboxylic acid 1
• 1-dioxide
• glycine binding site
• N-methyl-d-aspartate receptor
• structure–activity relationship

Acknowledgements

The authors thank Tanja Bauer and Sabine Denk for their expert technical assistance in performing the in vitro experiments.

Declaration of interest

The authors declare no conflicts of interest.

This work was financially supported by Merz Pharmaceuticals GmbH.

Supplementary material available online

Supplementary Information