[2.2]Paracyclophane‐Based TCN‐201 Analogs as GluN2A‐Selective NMDA Receptor Antagonists

Abstract

Recent studies have shown the involvement of GluN2A subunit‐containing NMDA receptors in various neurological and pathological disorders. In the X‐ray crystal structure, TCN‐201 (1) and analogous pyrazine derivatives 2 and 3 adopt a U‐shape (hairpin) conformation within the binding site formed by the ligand binding domains of the GluN1 and GluN2A subunits. In order to mimic the resulting π/π‐interactions of two aromatic rings in the binding site, a [2.2]paracyclophane system was designed to lock these aromatic rings in a parallel orientation. Acylation of [2.2]paracyclophane (5) with oxalyl chloride and chloroacetyl chloride and subsequent transformations led to the oxalamide 7, triazole 10 and benzamides 12. The GluN2A inhibitory activities of the paracyclophane derivatives were tested with two‐electrode voltage clamp electrophysiology using Xenopus laevis oocytes expressing selectively functional NMDA receptors with GluN2A subunit. The o‐iodobenzamide 12 b with the highest similarity to TCN‐201 showed the highest GuN2A inhibitory activity of this series of compounds. At a concentration of 10 μM, 12 b reached 36 % of the inhibitory activity of TCN‐201 (1). This result indicates that the [2.2]paracyclophane system is well accepted by the TCN‐201 binding site.

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

“…In TEVC experiments, the [2.2]paracyclophane 6 (Figure 4) revealed approximately 36 % inhibitory activity of TCN-201 (1) at GluN2A-NMDA receptors. [27] In the reported series of ligands, the [2.2]paracyclophane system was functionalized at the aromatic ring, as displayed for benzamide 6. To better mimic the p-disubstituted ring B of TCN-201, the ring C imitating substituent should be attached to…”

“…(Figure 4) Furthermore, replacement of benzene rings A and B by the conformationally constrained [2.2]paracyclophane system was tolerated by the NMDA receptor. In TEVC experiments, the [2.2]paracyclophane 6 (Figure 4) revealed approximately 36 % inhibitory activity of TCN‐201 ( 1 ) at GluN2A‐NMDA receptors [27] …”

“…In TEVC experiments, the [2.2]paracyclophane 6 (Figure 4 ) revealed approximately 36 % inhibitory activity of TCN‐201 ( 1 ) at GluN2A‐NMDA receptors. [27] …”

The concise synthesis and resolution of planar chiral [2.2]paracyclophane oxazolines by C–H activation

“…[2.2]Paracyclophane 1 (X = H; Scheme 1) has garnered considerable attention as the core for planar chiral pre-ligands, 1,2 catalysts, 3,4 bioactive entities 5,6 and chiroptical materials. 7,8 The rigidity of the [2.2]paracyclophane provides an almost unrivalled opportunity to control the relative spatial position of various functional groups through a series of regioisomers.…”