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Abstract GluN2A containing N -methyl- D -aspartate receptors (NMDARs) are important ion channels in the central nervous system and highly involved in several different neurophysiological but also neuropathophysiological processes. However, current understanding of the contribution of GluN2A containing NMDARs in these processes is incomplete. Therefore, highly selective compounds are required to further investigate these ion channels. In 2010, TCN-201 (2), one of the first selective negative allosteric modulators was reported. While the binding site of 2 and the influence of the substitution pattern of the benzenesulfonamide part has been reported recently, detailed structure-activity-relationships of the diacylhydrazine part and the linked phenyl moiety are still missing. In order to examine the critical interactions between these moieties and the binding site, several TCN-201 analogs with modified diacylhydrazine part were synthesized. The negative allosteric effect was recorded by two-electrode voltage clamp (TEVC) experiments using GluN1a/GluN2A expressing Xenopus laevis oocytes. Our data led to the conclusion, that the terminal phenyl moiety is involved in a cation-π-interaction with the guanidinium moiety of Arg755 of the GluN1a subunit, which plays a crucial role for high activity. Additionally, structure optimization by replacing the phenyl moiety with a thiophen-2-yl (10c), indol-2-yl (10g) or indol-3-yl (10h) moiety significantly increased the activity of 2 by the factor 2.5. At a test compound concentration of 200 nM, the negative allosteric effect of the most potent ligands 10c, 10h and 17 was significantly influenced by the glycine concentration. Although glycine dependency is higher than those of the lead compound 4 , 10c and 17 showed significantly higher negative allosteric effects than 4 at glycine concentrations from 1 μM up to 10 μM. The potent GluN2A-NMDA receptor inhibitors 10c , 10h and 17 did not influence the ion current of GluN2B-NMDA receptors. Graphical abstract Image 1 Highlights • The benzoylhydrazine part of TCN-201 was modified systematically. • The GluN2A inhibitory activity was investigated in two-electrode voltage clamp experiments. • Ligands with thiophen-2-yl and indol-3-yl instead of phenyl moiety are potent NAMs of GluN2A-NMDA receptors. • A cation-π-interaction between the terminal aryl moiety and the guanidinium moiety of GluN1 Arg755 plays a crucial role. • High glycine concentration reduces the negative allosteric effect of TCN 201 analogs. [ABSTRACT FROM AUTHOR]

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 IC 50 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. [ABSTRACT FROM AUTHOR]

NMDA Receptors (NMDARs) play key roles in synaptic physiology and NMDAR hypofunction has been implicated in various neurological conditions. In recent years an increasing number of positive allosteric modulators (PAMs) of NMDARs have been discovered and characterized. These diverse PAM classes vary not only in their binding sites and GluN2 subunit selectivity profiles, but also in the nature of their impacts on channel function. Major differences exist in the degree of slowing of channel deactivation and shifting of apparent agonist affinity between different classes of PAMs. Here we review the diverse modes of potentiation by the currently known classes of NMDAR PAMs and discuss the potential consequences of different types of potentiation in terms of desirable and undesirable effects on brain function. This article is part of the Special Issue entitled ‘Ionotropic glutamate receptors’. [ABSTRACT FROM AUTHOR]

Glutamatergic N -Methyl- d -aspartate (NMDA) receptors are heterotetrameric ion channels that can be comprised of different subunits. GluN2A subunit-containing NMDA receptors are associated with diseases like anxiety, depression, and schizophrenia. However, the exact contribution of these NMDA receptor subtypes is still unclear. To understand better the role of the GluN2A-containing receptors, novel ligands were designed. In co-crystallization with the isolated binding site, TCN-201 (1) and analogs adopt a U-shape conformation with parallel orientation of rings A and B. In order to increase the π/π-interactions between these rings, ring B of TCN-201 was replaced bioisosterically by different electron-rich thiazole, oxazole, and isoxazole heterocycles. The inhibitory activity was measured by two-electrode voltage clamp experiments with Xenopus laevis oocytes expressing GluN2A-containing NMDA receptors. It was found that 21c , 31a , 37a , and 37b were able to inhibit the ion channel. The isoxazole derivative 37b was the most potent negative allosteric modulator displaying 40% of the TCN-201 activity at a concentration of 10 μM. Image 1 • NMDA receptors with GluN2A subunit are associated with various CNS diseases. • TCN-201 adopts a U-shape structure in the binding pocket. • Novel TCN-201 analogs with electron-rich ring B were synthesized. • π/π-Interactions between the electron-rich and –poor aromatic rings should reinforce the U-shape structure. • Oxazole and isoxazole analogs reach almost the activity of the lead compound TCN-201 in two-electrode voltage clamp experiments. [ABSTRACT FROM AUTHOR]