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

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

doi:10.1021/acs.jmedchem.8b01986

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

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

Research output: Contribution to journal › Article › peer-review

20 Scopus citations

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
Pages (from-to)	4467-4482
Number of pages	16
Journal	Journal of Medicinal Chemistry
Volume	62
Issue number	9
DOIs	https://doi.org/10.1021/acs.jmedchem.8b01986
State	Published - May 9 2019

Funding

This research was supported by funds from the University of Turin, Ricerca Locale 2016/2017 (grant nos LOLM_RI-LO_17_01, BOSD_RILO_17_01), Ministero dell’Istruzione, dell’Università e della Ricerca PRIN 2015 (LOLM_-PRIN_2015_16_01), the Lundbeck Foundation. (P.T., S.M., and J.S.K.), Danscatt (S.M., J.S.K., D.S.P.), and by the NIH (GM103546 and NS097536) to K.B.H. We wish to thank Dr. Livio Stevanato for performing all of the NMR experiments and for instrument maintenance and Heidi Peterson for help with expression, purification, and crystallization. We wish to thank beamline scientists at BioMAX, MAXIV, Lund, Sweden, for excellent support during data collections. This research was supported by funds from the University of Turin, Ricerca Locale 2016/2017 (grant nos LOLM-RILO-17-01, BOSD-RILO-17-01), Ministero dell'Istruzione, dell'Universit? e della Ricerca PRIN 2015 (LOLM-PRIN-2015-16-01), the Lundbeck Foundation. (P.T., S.M., and J.S.K.), Danscatt (S.M., J.S.K., D.S.P.), and by the NIH (GM103546 and NS097536) to K.B.H. We wish to thank Dr. Livio Stevanato for performing all of the NMR experiments and for instrument maintenance and Heidi Peterson for help with expression, purification, and crystallization. We wish to thank beamline scientists at BioMAX, MAXIV, Lund, Sweden, for excellent support during data collections.

Funder number
PRIN 2015
LOLM_-PRIN_2015_16_01
2016/2017
GM103546
R01NS097536
LOLM_RI-LO_17_01, BOSD_RILO_17_01

Access to Document

10.1021/acs.jmedchem.8b01986

Cite this

Sainas, S., Temperini, P., Farnsworth, J. C., Yi, F., Møllerud, S., Jensen, A. A., Nielsen, B., Passoni, A., Kastrup, J. S., Hansen, K. B., Boschi, D., Pickering, D. S., Clausen, R. P., & Lolli, M. L. (2019). Use of the 4-Hydroxytriazole Moiety as a Bioisosteric Tool in the Development of Ionotropic Glutamate Receptor Ligands. Journal of Medicinal Chemistry, 62(9), 4467-4482. https://doi.org/10.1021/acs.jmedchem.8b01986

@article{ce1cfb938f774d15a7d2eb4dade2a668,

title = "Use of the 4-Hydroxytriazole Moiety as a Bioisosteric Tool in 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 Alice Passoni and Kastrup, \{Jette S.\} and Hansen, \{Kasper B.\} and Donatella Boschi and Pickering, \{Darryl S.\} and Clausen, \{Rasmus P.\} and Lolli, \{Marco L.\}",

note = "Publisher Copyright: {\textcopyright} 2019 American Chemical Society.",

year = "2019",

month = may,

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",

number = "9",

}

Sainas, S, Temperini, P, Farnsworth, JC, Yi, F, Møllerud, S, Jensen, AA, Nielsen, B, Passoni, A, Kastrup, JS, Hansen, KB, Boschi, D, Pickering, DS, Clausen, RP & Lolli, ML 2019, 'Use of the 4-Hydroxytriazole Moiety as a Bioisosteric Tool in the Development of Ionotropic Glutamate Receptor Ligands', Journal of Medicinal Chemistry, vol. 62, no. 9, pp. 4467-4482. https://doi.org/10.1021/acs.jmedchem.8b01986

TY - JOUR

T1 - Use of the 4-Hydroxytriazole Moiety as a Bioisosteric Tool in 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 - Passoni, Alice

AU - Kastrup, Jette S.

AU - Hansen, Kasper B.

AU - Boschi, Donatella

AU - Pickering, Darryl S.

AU - Clausen, Rasmus P.

AU - Lolli, Marco L.

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.

UR - https://www.scopus.com/pages/publications/85065096277

U2 - 10.1021/acs.jmedchem.8b01986

DO - 10.1021/acs.jmedchem.8b01986

M3 - Article

C2 - 30943028

AN - SCOPUS:85065096277

SN - 0022-2623

VL - 62

SP - 4467

EP - 4482

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 9

ER -

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

Abstract

Funding

Access to Document

Other files and links

Fingerprint

Cite this