Use of the 4‑Hydroxytriazole Moiety as a Bioisosteric Tool in the Development of Ionotropic Glutamate Receptor Ligands

We
report a series of glutamate and aspartate analogues designed
using the hydroxy-1,2,3-triazole moiety as a bioisostere for the distal
carboxylic acid. Compound 6b showed unprecedented selectivity
among (S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)­propionic
acid (AMPA) receptor subtypes, confirmed also by an unusual binding
mode observed for the crystal structures in complex with the AMPA
receptor GluA2 agonist-binding domain. Here, 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 N-methyl-d-aspartic acid receptor. These observations demonstrate novel
features that arise when employing a hydroxytriazole moiety as a bioisostere
for the distal carboxylic acid in glutamate receptor agonists.