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

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 - 2013/9

Y1 - 2013/9

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

SN - 1399-0047

SN - 2059-7983

VL - 69

SP - 1645

EP - 1652

JO - Acta crystallographica. Section D, Biological crystallography

JF - Acta crystallographica. Section D, Biological crystallography

IS - Pt 9

ER -