GluN2A‐Selective NMDA Receptor Antagonists: Mimicking the U‐Shaped Bioactive Conformation of TCN‐201 by a [2.2]Paracyclophane System. (13th October 2022)

• Record Type: Journal Article
• Authors: Steigerwald, Ruben; Chou, Tsung‐Han; Furukawa, Hiro; Wünsch, Bernhard
• Is Part Of: ChemMedChem. Volume 17:Number 21(2022)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2022-10-13
• Subjects: docking studies -- GluN2A -- NMDA receptors -- [2.2]paracyclophane -- TCN-201 -- two-electrode voltage clamp; Pharmaceutical chemistry -- Periodicals; 615.19005
• DOI: 10.1002/cmdc.202200484
• Languages: English
• ISSNs: 1860-7179

Abstract

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 for benzoic acid esters and benzamides. Abstract : In the X‐ray crystal structure, prototypical antagonists adopt a U‐shaped conformation within the binding site of GluN2A subunit containing NMDA receptors. [2.2]Paracyclophanes were designed and synthesized to mimic this unconventional conformation. Although docking studies revealed promising binding poses, the inhibition of the ion channel was rather low.