Use of the 4-Hydroxy-Triazole Moiety as a Bioisosteric Tool for the Development of Ionotropic Glutamate Receptor Ligands
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Use of the 4-Hydroxy-Triazole Moiety as a Bioisosteric Tool for the Development of Ionotropic Glutamate Receptor Ligands. / Sainas, Stefano; Temperini, Piero; Farnsworth, Jill C; Yi, Feng; Møllerud, Stine; Jensen, Anders A.; Nielsen, Birgitte; Kastrup, Jette Sandholm Jensen; Hansen, Kasper B; Boschi, Donatella; Pickering, Darryl S; Clausen, Rasmus Prætorius; Lolli, Marco.
In: Journal of Medicinal Chemistry, Vol. 62, 2019, p. 4467-4482.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Use of the 4-Hydroxy-Triazole Moiety as a Bioisosteric Tool for the Development of Ionotropic Glutamate Receptor Ligands
AU - Sainas, Stefano
AU - Temperini, Piero
AU - Farnsworth, Jill C
AU - Yi, Feng
AU - Møllerud, Stine
AU - Jensen, Anders A.
AU - Nielsen, Birgitte
AU - Kastrup, Jette Sandholm Jensen
AU - Hansen, Kasper B
AU - Boschi, Donatella
AU - Pickering, Darryl S
AU - Clausen, Rasmus Prætorius
AU - Lolli, Marco
PY - 2019
Y1 - 2019
N2 - 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.
AB - 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.
U2 - 10.1021/acs.jmedchem.8b01986
DO - 10.1021/acs.jmedchem.8b01986
M3 - Journal article
C2 - 30943028
VL - 62
SP - 4467
EP - 4482
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
ER -
ID: 213096829