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

Research output: Contribution to journalJournal articleResearchpeer-review

Standard

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, 09.05.2019, p. 4467-4482.

Research output: Contribution to journalJournal articleResearchpeer-review

Harvard

Sainas, S, Temperini, P, Farnsworth, JC, Yi, F, Møllerud, S, Jensen, AA, Nielsen, B, Kastrup, JSJ, Hansen, KB, Boschi, D, Pickering, DS, Clausen, RP & Lolli, M 2019, 'Use of the 4-Hydroxy-Triazole Moiety as a Bioisosteric Tool for the Development of Ionotropic Glutamate Receptor Ligands', Journal of Medicinal Chemistry, vol. 62, pp. 4467-4482. https://doi.org/10.1021/acs.jmedchem.8b01986

APA

Sainas, S., Temperini, P., Farnsworth, J. C., Yi, F., Møllerud, S., Jensen, A. A., ... Lolli, M. (2019). Use of the 4-Hydroxy-Triazole Moiety as a Bioisosteric Tool for the Development of Ionotropic Glutamate Receptor Ligands. Journal of Medicinal Chemistry, 62, 4467-4482. https://doi.org/10.1021/acs.jmedchem.8b01986

Vancouver

Sainas S, Temperini P, Farnsworth JC, Yi F, Møllerud S, Jensen AA et al. Use of the 4-Hydroxy-Triazole Moiety as a Bioisosteric Tool for the Development of Ionotropic Glutamate Receptor Ligands. Journal of Medicinal Chemistry. 2019 May 9;62:4467-4482. https://doi.org/10.1021/acs.jmedchem.8b01986

Author

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. / Use of the 4-Hydroxy-Triazole Moiety as a Bioisosteric Tool for the Development of Ionotropic Glutamate Receptor Ligands. In: Journal of Medicinal Chemistry. 2019 ; Vol. 62. pp. 4467-4482.

Bibtex

@article{696096224f9e4dc0b7e09268c700ae7e,
title = "Use of the 4-Hydroxy-Triazole Moiety as a Bioisosteric Tool for the Development of Ionotropic Glutamate Receptor Ligands",
abstract = "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.",
author = "Stefano Sainas and Piero Temperini and Farnsworth, {Jill C} and Feng Yi and Stine M{\o}llerud and Jensen, {Anders A.} and Birgitte Nielsen and Kastrup, {Jette Sandholm Jensen} and Hansen, {Kasper B} and Donatella Boschi and Pickering, {Darryl S} and Clausen, {Rasmus Pr{\ae}torius} and Marco Lolli",
year = "2019",
month = "5",
day = "9",
doi = "10.1021/acs.jmedchem.8b01986",
language = "English",
volume = "62",
pages = "4467--4482",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",

}

RIS

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 - 2019/5/9

Y1 - 2019/5/9

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