GluN2A-selective NMDA receptor antagonists: Mimicking the U-shaped bioactive conformation of TCN-201 by a [2.2]paracyclophane system

Steigerwald, Ruben, Chou, Tsung-Han, Furukawa, Hiro, Wünsch, Bernhard (September 2022) GluN2A-selective NMDA receptor antagonists: Mimicking the U-shaped bioactive conformation of TCN-201 by a [2.2]paracyclophane system. ChemMedChem: chemistry enabling drug discovery. ISSN 1860-7179

Preview

PDF ChemMedChem - 2022 - Steigerwald - GluN2A‐Selective NMDA Receptor Antagonists Mimicking the U‐Shaped Bioactive.pdf Available under License Creative Commons Attribution Non-commercial. Download (1MB) | Preview

Abstract

Under physiological conditions, N -Methyl- D - A spartate (NMDA) receptors play a crucial role for synaptic plasticity, long-term potentiation and long-term depression. However, overactivation of NMDA receptors can result in excitotoxicity, which is associated with various neurological and neurodegenerative diseases. The physiological properties of NMDA receptors are strongly dependent on the GluN2 subunit incorporated into the heterotetrameric NMDA receptor. Therefore, subtype selective NMDA receptor modulators are of high interest. Since prototypical GluN2A-NMDA receptor antagonists TCN-201 and its MPX-analogs adopt a U-shaped conformation within the binding pocket, paracyclophanes were designed containing the phenyl rings in an already parallel orientation. Docking studies of the designed paracyclophanes show a similar binding pose as TCN-201. [2.2]Paracyclophanes with a benzoate or benzamide side chain were prepared in four-step synthesis, respectively, starting with a radical bromination in benzylic 1-position of [2.2]paracyclophane. In two-electrode voltage clamp experiments using Xenopus laevis oocytes transfected with cRNAs for the GluN1-4a and GluN2A subunits, the esters and amides (conc. 10 µM) did not show considerable inhibition of ion flux. It can be concluded that the GluN2A-NMDA receptor does not accept ligands with a paracyclophane scaffold functionalized in benzylic 1-position, although docking studies had revealed promising binding poses.

Item Type:	Paper
Subjects:	bioinformatics organism description > animal > Frog bioinformatics > genomics and proteomics > genetics & nucleic acid processing bioinformatics > genomics and proteomics bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types > NMDA receptor bioinformatics > genomics and proteomics > small molecules > NMDA receptor bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification organism description > animal bioinformatics > genomics and proteomics > genetics & nucleic acid processing > protein structure, function, modification > protein types bioinformatics > genomics and proteomics > small molecules organism description > animal > Frog > xenopus
CSHL Authors:	Furukawa, Hiro Chou, Tsung-Han Steigerwald, Ruben
Communities:	CSHL labs > Furukawa lab
SWORD Depositor:	CSHL Elements
Depositing User:	CSHL Elements
Date:	28 September 2022
Date Deposited:	07 Oct 2022 00:39
Last Modified:	02 May 2024 19:59
PMCID:	PMC9828697
URI:	https://repository.cshl.edu/id/eprint/40730

Actions (login required)

Administrator's edit/view item