Use of the 4-Hydroxy-Triazole Moiety as a Bioisosteric Tool for the Development of Ionotropic Glutamate Receptor Ligands

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We report the synthesis and pharmacological characterization of a small series of glutamate and aspartate analogues using the hydroxy-1,2,3-triazole moiety as a bioisostere for the distal carboxylic acid. One analogue (6b) showed unprecedented selectivity among AMPA receptor subtypes and crystal structures of the AMPA receptor GluA2 agonist binding domain in complex with 6b and 7a revealed unusual binding modes. In the structure with 6b in the GluA2 agonist binding domain, a methionine (Met729) was highly disordered compared to previous agonist-bound structures. This observation provides a possible explanation for the pharmacological profile. In the structure with 7a, an unusual organization of water molecules around the bioisostere arises compared to previous structures of ligands with other bioisosteres. Aspartate analogue 8 with the hydroxy-1,2,3-triazole moiety directly attached to glycine was unexpectedly able to activate both the glutamate and glycine agonist binding sites of the NMDA receptor. These observations demonstrate novel features that can arise when employing a hydroxyl-triazole moiety as bioisostere for the distal carboxylic acid in glutamate receptor agonists.
Original languageEnglish
JournalJournal of Medicinal Chemistry
Pages (from-to)4467-4482
Publication statusPublished - 2019

ID: 213096829