Synthesis of GluN2A-selective NMDA receptor antagonists with an electron-rich aromatic B-ring

Rajan, Remya; Schepmann, Dirk; Schreiber, Julian A.; Seebohm, Guiscard; Wünsch, Bernhard

doi:10.1016/j.ejmech.2020.112939

Cited by 4 publications

(4 citation statements)

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“…The antagonistic activity of the [2.2]paracyclophane derivatives was tested by two‐electrode voltage clamp (TEVC) using Xenopus laevis oocytes as previously described. [ 25 , 26 , 27 ] cRNAs for the GluN1a and GluN2A subunits were injected into defolliculated oocytes and the oocytes were incubated at 16 °C for 4 days. The membrane current due to NMDA receptor activation, which was achieved with 10 μM ( S )‐glutamate and 10 μM glycine, was recorded.…”

Section: Resultsmentioning

confidence: 99%

“…Molecular biology and TEVC experiments were conducted as previously described. [ 25 , 26 , 27 ] Measurements were performed using a Turbo Tec 10CX amplifier (NPI electronic, Tamm, Germany), NI USB 6221 DA/AD Interface (National Instruments, Austin, USA) and GePulse Software (Dr. Michael Pusch, Genova, Italy). All experiments were conducted at room temperature.…”

Section: Methodsmentioning

confidence: 99%

“…Even though MPX‐004 ( 2 ) and MPX‐007 ( 3 ) showed higher inhibitory activity at GluN2A NMDA receptors (IC 50 ( 2 )=79 nM, IC 50 ( 3 )=27 nM) than TCN‐201, the inhibitory activity of 2 and 3 was also reduced by high concentrations of glycine [24] . (Figure 1) Replacement of the benzene ring in the middle of TCN‐201 by electron‐rich five‐membered aromatic heterocycles such as thiazole, oxazole and isoxazole rings led to reduced GluN2A NMDA inhibition [25] . However, systematic modifications of the benzenesulfonamide ]26] and the benzoylhydrazine moiety ]27] of TCN‐201 could slightly improve the inhibitory activity at GluN2A containing NMDA receptors.…”

Section: Introductionmentioning

confidence: 99%

“… [24] (Figure 1 ) Replacement of the benzene ring in the middle of TCN‐201 by electron‐rich five‐membered aromatic heterocycles such as thiazole, oxazole and isoxazole rings led to reduced GluN2A NMDA inhibition. [25] However, systematic modifications of the benzenesulfonamide ]26] and the benzoylhydrazine moiety ]27] of TCN‐201 could slightly improve the inhibitory activity at GluN2A containing NMDA receptors.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2021

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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.

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Section: Resultsmentioning

confidence: 99%