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

Stefano Sainas; Piero Temperini; Jill C Farnsworth; Feng Yi; Stine Møllerud; Anders A. Jensen; Birgitte Nielsen; Jette Sandholm Jensen Kastrup; Kasper B Hansen; Donatella Boschi; Darryl S Pickering; Rasmus Prætorius Clausen; Marco Lolli

doi:10.1021/acs.jmedchem.8b01986

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

Stefano Sainas, Piero Temperini, Jill C Farnsworth, Feng Yi, Stine Møllerud, Anders A. Jensen, Birgitte Nielsen, Jette Sandholm Jensen Kastrup, Kasper B Hansen, Donatella Boschi, Darryl S Pickering, Rasmus Prætorius Clausen, Marco Lolli

11 Citations (Scopus)

Abstract

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.

Original language	English
Journal	Journal of Medicinal Chemistry
Volume	62
Pages (from-to)	4467-4482
Number of pages	14
ISSN	0022-2623
DOIs	https://doi.org/10.1021/acs.jmedchem.8b01986
Publication status	Published - 9 May 2019

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Sainas, S., Temperini, P., Farnsworth, J. C., Yi, F., Møllerud, S., Jensen, A. A., Nielsen, B., Kastrup, J. S. J., Hansen, K. B., Boschi, D., Pickering, D. S., Clausen, R. P., & 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

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

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

abstract = "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.",

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",

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doi = "10.1021/acs.jmedchem.8b01986",

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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 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.

AB - 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.

U2 - 10.1021/acs.jmedchem.8b01986

DO - 10.1021/acs.jmedchem.8b01986

M3 - Journal article

C2 - 30943028

SN - 0022-2623

VL - 62

SP - 4467

EP - 4482

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

ER -

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

Abstract

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