Positive allosteric modulators of the ionotropic glutamate receptor-2 (GluA2) are promising compounds for the treatment of cognitive disorders, e.g. Alzheimer's disease. These modulators bind within the dimer interface of the LBD (ligand-binding domain) and stabilize the agonist-bound conformation slowing receptor desensitization and/or deactivation. In the present study, we employ isothermal titration calorimetry to determine binding affinities and thermodynamic details of binding of modulators of GluA2. A mutant of the LBD of GluA2 (LBD-L483Y-N754S) that forms a stable dimer in solution was used. The potent GluA2 modulator BPAM-97 was used as a reference compound. Evidence that BPAM-97 binds in the same pocket as the well-known GluA2 modulator cyclothiazide was obtained from X-ray structures. The LBD-L483Y-N754S:BPAM-97 complex has a Kd of 5.6 μM (ΔH=−4.9 kcal/mol, −TΔS=−2.3 kcal/mol; where 1 kcal≈4.187 kJ). BPAM-97 was used in a displacement assay to determine a Kd of 0.46 mM (ΔH=−1.2 kcal/mol, −TΔS=−3.3 kcal/mol) for the LBD-L483Y-N754S:IDRA-21 complex. The major structural factors increasing the potency of BPAM-97 over IDRA-21 are the increased van der Waals contacts to, primarily, Met496 in GluA2 imposed by the ethyl substituent of BPAM-97. These results add important information on binding affinities and thermodynamic details, and provide a new tool in the development of drugs against cognitive disorders.
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Research Article|
December 14 2011
Thermodynamics and structural analysis of positive allosteric modulation of the ionotropic glutamate receptor GluA2
Christian Krintel;
Christian Krintel
*Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark
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Karla Frydenvang;
Karla Frydenvang
*Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark
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Lars Olsen;
Lars Olsen
*Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark
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Maria T. Kristensen;
Maria T. Kristensen
*Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark
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Oriol de Barrios;
Oriol de Barrios
*Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark
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Peter Naur;
Peter Naur
*Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark
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Pierre Francotte;
Pierre Francotte
†Drug Research Center, Laboratoire de chimie Pharmaceutique, Université de Liège. Av. De l' Hôpital, 1, B36, 4000 Liège, Belgium
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Bernard Pirotte;
Bernard Pirotte
†Drug Research Center, Laboratoire de chimie Pharmaceutique, Université de Liège. Av. De l' Hôpital, 1, B36, 4000 Liège, Belgium
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Michael Gajhede;
Michael Gajhede
*Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark
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Jette S. Kastrup
Jette S. Kastrup
1
*Department of Medicinal Chemistry, Faculty of Pharmaceutical Sciences, University of Copenhagen, Universitetsparken 2, DK-2100 Copenhagen, Denmark
1To whom correspondence should be addressed (email jsk@farma.ku.dk).
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Publisher: Portland Press Ltd
Received:
July 07 2011
Revision Received:
August 30 2011
Accepted:
September 07 2011
Accepted Manuscript online:
September 07 2011
Online ISSN: 1470-8728
Print ISSN: 0264-6021
© The Authors Journal compilation © 2012 Biochemical Society
2012
Biochem J (2012) 441 (1): 173–178.
Article history
Received:
July 07 2011
Revision Received:
August 30 2011
Accepted:
September 07 2011
Accepted Manuscript online:
September 07 2011
Citation
Christian Krintel, Karla Frydenvang, Lars Olsen, Maria T. Kristensen, Oriol de Barrios, Peter Naur, Pierre Francotte, Bernard Pirotte, Michael Gajhede, Jette S. Kastrup; Thermodynamics and structural analysis of positive allosteric modulation of the ionotropic glutamate receptor GluA2. Biochem J 1 January 2012; 441 (1): 173–178. doi: https://doi.org/10.1042/BJ20111221
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