Structural analysis of the positive AMPA receptor modulators CX516 and Me-CX516 in complex with the GluA2 ligand-binding domain
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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; Peters, Dan; Frydenvang, Karla; Pickering, Darryl S; Gajhede, Michael; Kastrup, Jette S.
In: Acta Crystallographica Section D: Structural Biology, Vol. 69, No. Pt 9, 2013, p. 1645-1652.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Structural analysis of the positive AMPA receptor modulators CX516 and Me-CX516 in complex with the GluA2 ligand-binding domain
AU - Krintel, Christian
AU - Harpsøe, Kasper
AU - Zachariassen, Linda G
AU - Peters, Dan
AU - Frydenvang, Karla
AU - Pickering, Darryl S
AU - Gajhede, Michael
AU - Kastrup, Jette S
PY - 2013
Y1 - 2013
N2 - 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.
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.
KW - Allosteric Regulation
KW - Animals
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
U2 - 10.1107/S0907444913011839
DO - 10.1107/S0907444913011839
M3 - Journal article
C2 - 23999288
VL - 69
SP - 1645
EP - 1652
JO - Acta Crystallographica Section D: Structural Biology
JF - Acta Crystallographica Section D: Structural Biology
SN - 2059-7983
IS - Pt 9
ER -
ID: 107359115