Negative allosteric modulators of the GluN2B NMDA receptor with phenylethylamine structure embedded in ring-expanded and ring-contracted scaffolds.

Louisa Temme, Elena Bechthold, Julian A Schreiber, Sandeep Gawaskar, Dirk Schepmann, Dina Robaa, Wolfgang Sippl, Guiscard Seebohm, Bernhard Wünsch

European journal of medicinal chemistry 2020 Mar 15

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A set of GluN2B NMDA receptor antagonists with conformationally restricted phenylethylamine substructure was prepared and pharmacologically evaluated. The phenylethylamine substructure was embedded in ring expanded 3-benzazocines 4 as well as ring-contracted tetralinamines 6 and indanamines 7. The ligands 4, 6 and 7 were synthesized by reductive alkylation of secondary amine 11, reductive amination of ketones 12 and 16 and nucleophilic substitution of nosylates 14 and 17. The moderate GluN2B affinity of 3-benzazocine 4d (Ki = 32 nM) translated into moderate cytoprotective activity (IC50 = 890 nM) and moderate ion channel inhibition (60% at 10 μM) in two-electrode voltage clamp experiments with GluN1a/GluN2B expressing oocytes. Although some of the tetralinamines 6 and indanamines 7 showed very high GluN2B affinity (e.g. Ki (7f) = 3.2 nM), they could not inhibit glutamate/glycine inducted cytotoxicity. The low cytoprotective activity of 3-benzazocines 4, tetralinamines 6 and indanamines 7 was attributed to the missing OH moiety at the benzene ring and/or in benzylic position. Docking studies showed that the novel GluN2B ligands adopt similar binding poses as Ro 25-6981 with the central H-bond interaction between the protonated amino moiety of the ligands and the carbamoyl moiety of Gln110. However, due to the lack of a second H-bond forming group, the ligands can adopt two binding poses within the ifenprodil binding pocket. Copyright © 2020 Elsevier Masson SAS. All rights reserved.

Citation

Louisa Temme, Elena Bechthold, Julian A Schreiber, Sandeep Gawaskar, Dirk Schepmann, Dina Robaa, Wolfgang Sippl, Guiscard Seebohm, Bernhard Wünsch. Negative allosteric modulators of the GluN2B NMDA receptor with phenylethylamine structure embedded in ring-expanded and ring-contracted scaffolds. European journal of medicinal chemistry. 2020 Mar 15;190:112138