GluN2A‐Selective NMDA Receptor Antagonists: Mimicking the U‐Shaped Bioactive Conformation of TCN‐201 by a [2.2]Paracyclophane System

Abstract

Under physiological conditions, N‐Methyl‐D‐Aspartate (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.

GluN2A and GluN2B N-Methyl-D-Aspartate Receptor (NMDARs) Subunits: Their Roles and Therapeutic Antagonists in Neurological Diseases

“…Nevertheless, their selectivity at a high concentration (10 uM) was lower than the one observed for TCN-201 since both MPX-004 and MPX-007 inhibited GluN2B current (at 10 uM) by 8% and 30% respectively [113]. TCN-201, a GluN2A NMDAR antagonist, looks more promising as a superior phar macological tool for investigating the roles of GluN2A, since it has higher selectivity for GluN2A compared to GluN2B [113,118], probably because of the interactions at the ligand binding domains (LBDs) of GluN1 and GluN2A subunits. TCN-201′s binding site location is proposed to be at the interface between the LBDs of GluN1 and GluN2A subunits [119] Modulation of LBD interactions has shown promising therapeutic potential.…”

“…X-ray crystallog raphy results indicated that these compounds bind to a site situated at the interface be tween the GluN1 and GluN2A subunit LBDs [80,123]. TCN-201, a GluN2A NMDAR antagonist, looks more promising as a superior pharmacological tool for investigating the roles of GluN2A, since it has higher selectivity for GluN2A compared to GluN2B [113,118], probably because of the interactions at the ligand binding domains (LBDs) of GluN1 and GluN2A subunits. TCN-201 s binding site location is proposed to be at the interface between the LBDs of GluN1 and GluN2A subunits [119].…”