2. Academic Validation
  3. Systematic variation of the benzenesulfonamide part of the GluN2A selective NMDA receptor antagonist TCN-201

Systematic variation of the benzenesulfonamide part of the GluN2A selective NMDA receptor antagonist TCN-201

  • Eur J Med Chem. 2017 Mar 31:129:124-134. doi: 10.1016/j.ejmech.2017.02.018.
Sebastian L Müller 1,  Julian A Schreiber 1,  Dirk Schepmann 1,  Nathalie Strutz-Seebohm 2,  Guiscard Seebohm 2,  Bernhard Wünsch 3
Affiliations

Affiliations

  • 1 Institute of Pharmaceutical and Medicinal Chemistry, University of Münster, Corrensstr. 48, D-48149 Münster, Germany.
  • 2 Institute for Genetics of Heart Diseases (IfGH), Department of Cardiovascular Medicine, University Hospital Muenster, D-48149 Muenster, Germany.
  • 3 Institute of Pharmaceutical and Medicinal Chemistry, University of Münster, Corrensstr. 48, D-48149 Münster, Germany; Cells-in-Motion Cluster of Excellence (EXC 1003 - CiM), University Münster, Germany. Electronic address: wuensch@uni-muenster.de.
PMID: 28222314 DOI: 10.1016/j.ejmech.2017.02.018
Abstract

GluN2A subunit containing N-methyl-d-aspartate receptors (NMDARs) are highly involved in various physiological processes in the central nervous system, but also in some diseases, such as anxiety, depression and schizophrenia. However, the role of GluN2A subunit containing NMDARs in pathological processes is not exactly elucidated. In order to obtain potent and selective inhibitors of GluN2A subunit containing NMDARs, the selective negative allosteric modulator 2 was systematically modified at the benzenesulfonamide part. The activity of the test compounds was recorded in two electrode voltage clamp experiments using Xenopus laevis oocytes expressing exclusively NMDARs with GluN1a and GluN2A subunits. It was found that halogen atoms in 3-position of the benzenesulfonamide part result in high GluN2A antagonistic activity. With an IC50 value of 204 nM the 3-bromo derivative 5i (N-{4-[(2-benzoylhydrazino)carbonyl]benzyl}-3-bromobenzenesulfonamide) has 2.5-fold higher antagonistic activity than the lead compound 2 and represents our new lead compound.

Keywords

Antagonistic activity; Electrophysiology; GluN2A selective antagonists; NMDA receptor; Structure activity relationships; Synthesis; TCN-201; Two electrode voltage clamp.

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