Structural analysis of the positive AMPA receptor modulators CX516 and Me-CX516 in complex with the GluA2 ligand-binding domain

Christian Krintel; Kasper Harpsøe; Linda G Zachariassen; Dan Peters; Karla Frydenvang; Darryl S Pickering; Michael Gajhede; Jette S Kastrup

doi:10.1107/s0907444913011839

Structural analysis of the positive AMPA receptor modulators CX516 and Me-CX516 in complex with the GluA2 ligand-binding domain

Christian Krintel, Kasper Harpsøe, Linda G Zachariassen, Dan Peters, Karla Frydenvang, Darryl S Pickering, Michael Gajhede, Jette S Kastrup

Novo Nordisk Foundation Center for Protein Research

8 Citations (Scopus)

Abstract

Positive allosteric modulators of the ionotropic glutamate receptor A2 (GluA2) can serve as lead compounds for the development of cognitive enhancers. Several benzamide-type (S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptor modulators such as aniracetam, CX516 and CX614 have been shown to inhibit the deactivation of AMPA receptors with a less pronounced effect on desensitization. Despite CX516 being an extensively investigated AMPA receptor modulator and one of the few clinically evaluated compounds, the binding mode of CX516 to AMPA receptors has not been reported. Here, the structures of a GluA2 ligand-binding domain mutant in complex with CX516 and the 3-methylpiperidine analogue of CX516 (Me-CX516) are reported. The structures show that the binding modes of CX516 and Me-CX516 are similar to those of aniracetam and CX614 and that there is limited space for substitution at the piperidine ring of CX516. The results therefore support that CX516, like aniracetam and CX614, modulates deactivation of AMPA receptors.

Original language	English
Journal	Acta crystallographica. Section D, Biological crystallography
Volume	69
Issue number	Pt 9
Pages (from-to)	1645-52
Number of pages	8
DOIs	https://doi.org/10.1107/s0907444913011839
Publication status	Published - Sept 2013

Keywords

Allosteric Regulation
Animals
Crystallography, X-Ray
Dioxoles
Ligands
Macromolecular Substances
Mutation
Oxazines
Piperidines
Protein Binding
Protein Interaction Mapping
Protein Structure, Tertiary
Rats
Receptors, AMPA

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Krintel, C., Harpsøe, K., Zachariassen, L. G., Peters, D., Frydenvang, K., Pickering, D. S., Gajhede, M., & Kastrup, J. S. (2013). Structural analysis of the positive AMPA receptor modulators CX516 and Me-CX516 in complex with the GluA2 ligand-binding domain. Acta crystallographica. Section D, Biological crystallography, 69(Pt 9), 1645-52. https://doi.org/10.1107/s0907444913011839

Structural analysis of the positive AMPA receptor modulators CX516 and Me-CX516 in complex with the GluA2 ligand-binding domain. / Krintel, Christian; Harpsøe, Kasper ; Zachariassen, Linda G et al.

In: Acta crystallographica. Section D, Biological crystallography, Vol. 69, No. Pt 9, 09.2013, p. 1645-52.

Research output: Contribution to journal › Journal article › Research › peer-review

Krintel, C, Harpsøe, K , Zachariassen, LG, Peters, D, Frydenvang, K , Pickering, DS , Gajhede, M & Kastrup, JS 2013, 'Structural analysis of the positive AMPA receptor modulators CX516 and Me-CX516 in complex with the GluA2 ligand-binding domain', Acta crystallographica. Section D, Biological crystallography, vol. 69, no. Pt 9, pp. 1645-52. https://doi.org/10.1107/s0907444913011839

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abstract = "Positive allosteric modulators of the ionotropic glutamate receptor A2 (GluA2) can serve as lead compounds for the development of cognitive enhancers. Several benzamide-type (S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptor modulators such as aniracetam, CX516 and CX614 have been shown to inhibit the deactivation of AMPA receptors with a less pronounced effect on desensitization. Despite CX516 being an extensively investigated AMPA receptor modulator and one of the few clinically evaluated compounds, the binding mode of CX516 to AMPA receptors has not been reported. Here, the structures of a GluA2 ligand-binding domain mutant in complex with CX516 and the 3-methylpiperidine analogue of CX516 (Me-CX516) are reported. The structures show that the binding modes of CX516 and Me-CX516 are similar to those of aniracetam and CX614 and that there is limited space for substitution at the piperidine ring of CX516. The results therefore support that CX516, like aniracetam and CX614, modulates deactivation of AMPA receptors.",

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AU - Peters, Dan

AU - Frydenvang, Karla

AU - Pickering, Darryl S

AU - Gajhede, Michael

AU - Kastrup, Jette S

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AB - Positive allosteric modulators of the ionotropic glutamate receptor A2 (GluA2) can serve as lead compounds for the development of cognitive enhancers. Several benzamide-type (S)-2-amino-3-(3-hydroxy-5-methyl-4-isoxazolyl)propionic acid (AMPA) receptor modulators such as aniracetam, CX516 and CX614 have been shown to inhibit the deactivation of AMPA receptors with a less pronounced effect on desensitization. Despite CX516 being an extensively investigated AMPA receptor modulator and one of the few clinically evaluated compounds, the binding mode of CX516 to AMPA receptors has not been reported. Here, the structures of a GluA2 ligand-binding domain mutant in complex with CX516 and the 3-methylpiperidine analogue of CX516 (Me-CX516) are reported. The structures show that the binding modes of CX516 and Me-CX516 are similar to those of aniracetam and CX614 and that there is limited space for substitution at the piperidine ring of CX516. The results therefore support that CX516, like aniracetam and CX614, modulates deactivation of AMPA receptors.

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KW - Crystallography, X-Ray

KW - Dioxoles

KW - Ligands

KW - Macromolecular Substances

KW - Mutation

KW - Oxazines

KW - Piperidines

KW - Protein Binding

KW - Protein Interaction Mapping

KW - Protein Structure, Tertiary

KW - Rats

KW - Receptors, AMPA

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JO - Acta Crystallographica Section D: Structural Biology

JF - Acta Crystallographica Section D: Structural Biology

IS - Pt 9

ER -

Structural analysis of the positive AMPA receptor modulators CX516 and Me-CX516 in complex with the GluA2 ligand-binding domain

Abstract

Keywords

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