Synthesis, pharmacological and structural characterization, and thermodynamic aspects of GluA2-positive allosteric modulators with a 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide scaffold

Research output: Contribution to journalJournal articleResearch

Standard

Synthesis, pharmacological and structural characterization, and thermodynamic aspects of GluA2-positive allosteric modulators with a 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide scaffold. / Nørholm, Ann-Beth; Francotte, Pierre; Olsen, Lars; Krintel, Christian; Frydenvang, Karla; Goffin, Eric; Challal, Sylvie; Danober, Laurence; Botez-Pop, Iuliana; Lestage, Pierre; Pirotte, Bernard; Kastrup, Jette S.

In: Journal of Medicinal Chemistry, Vol. 56, No. 21, 14.11.2013, p. 8736-45.

Research output: Contribution to journalJournal articleResearch

Harvard

Nørholm, A-B, Francotte, P, Olsen, L, Krintel, C, Frydenvang, K, Goffin, E, Challal, S, Danober, L, Botez-Pop, I, Lestage, P, Pirotte, B & Kastrup, JS 2013, 'Synthesis, pharmacological and structural characterization, and thermodynamic aspects of GluA2-positive allosteric modulators with a 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide scaffold', Journal of Medicinal Chemistry, vol. 56, no. 21, pp. 8736-45. https://doi.org/10.1021/jm4012092

APA

Nørholm, A-B., Francotte, P., Olsen, L., Krintel, C., Frydenvang, K., Goffin, E., ... Kastrup, J. S. (2013). Synthesis, pharmacological and structural characterization, and thermodynamic aspects of GluA2-positive allosteric modulators with a 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide scaffold. Journal of Medicinal Chemistry, 56(21), 8736-45. https://doi.org/10.1021/jm4012092

Vancouver

Nørholm A-B, Francotte P, Olsen L, Krintel C, Frydenvang K, Goffin E et al. Synthesis, pharmacological and structural characterization, and thermodynamic aspects of GluA2-positive allosteric modulators with a 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide scaffold. Journal of Medicinal Chemistry. 2013 Nov 14;56(21):8736-45. https://doi.org/10.1021/jm4012092

Author

Nørholm, Ann-Beth ; Francotte, Pierre ; Olsen, Lars ; Krintel, Christian ; Frydenvang, Karla ; Goffin, Eric ; Challal, Sylvie ; Danober, Laurence ; Botez-Pop, Iuliana ; Lestage, Pierre ; Pirotte, Bernard ; Kastrup, Jette S. / Synthesis, pharmacological and structural characterization, and thermodynamic aspects of GluA2-positive allosteric modulators with a 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide scaffold. In: Journal of Medicinal Chemistry. 2013 ; Vol. 56, No. 21. pp. 8736-45.

Bibtex

@article{40763218030444ab8c1574844b197120,
title = "Synthesis, pharmacological and structural characterization, and thermodynamic aspects of GluA2-positive allosteric modulators with a 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide scaffold",
abstract = "Positive allosteric modulators of ionotropic glutamate receptors are potential compounds for treatment of cognitive disorders, e.g., Alzheimer's disease. The modulators bind within the dimer interface of the ligand-binding domain (LBD) and stabilize the agonist-bound conformation, thereby slowing receptor desensitization and/or deactivation. Here we describe the synthesis and pharmacological testing at GluA2 of a new generation of 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides. The most potent modulator 3 in complex with GluA2-LBD-L483Y-N754S was subjected to structural analysis by X-ray crystallography, and the thermodynamics of binding was studied by isothermal titration calorimetry. Compound 3 binds to GluA2-LBD-L483Y-N754S with a Kd of 0.35 μM (ΔH = -7.5 kcal/mol and -TΔS = -1.3 kcal/mol). This is the first time that submicromolar binding affinity has been achieved for this type of positive allosteric modulator. The major structural factor increasing the binding affinity of 3 seems to be interactions between the cyclopropyl group of 3 and the backbone of Phe495 and Met496.",
keywords = "Allosteric Regulation, Animals, Benzothiadiazines, Calorimetry, Crystallography, X-Ray, Cyclic S-Oxides, Dose-Response Relationship, Drug, Models, Molecular, Molecular Structure, Neurons, Rats, Receptors, AMPA, Structure-Activity Relationship, Thermodynamics",
author = "Ann-Beth N{\o}rholm and Pierre Francotte and Lars Olsen and Christian Krintel and Karla Frydenvang and Eric Goffin and Sylvie Challal and Laurence Danober and Iuliana Botez-Pop and Pierre Lestage and Bernard Pirotte and Kastrup, {Jette S}",
year = "2013",
month = "11",
day = "14",
doi = "10.1021/jm4012092",
language = "English",
volume = "56",
pages = "8736--45",
journal = "Journal of Medicinal Chemistry",
issn = "0022-2623",
publisher = "American Chemical Society",
number = "21",

}

RIS

TY - JOUR

T1 - Synthesis, pharmacological and structural characterization, and thermodynamic aspects of GluA2-positive allosteric modulators with a 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide scaffold

AU - Nørholm, Ann-Beth

AU - Francotte, Pierre

AU - Olsen, Lars

AU - Krintel, Christian

AU - Frydenvang, Karla

AU - Goffin, Eric

AU - Challal, Sylvie

AU - Danober, Laurence

AU - Botez-Pop, Iuliana

AU - Lestage, Pierre

AU - Pirotte, Bernard

AU - Kastrup, Jette S

PY - 2013/11/14

Y1 - 2013/11/14

N2 - Positive allosteric modulators of ionotropic glutamate receptors are potential compounds for treatment of cognitive disorders, e.g., Alzheimer's disease. The modulators bind within the dimer interface of the ligand-binding domain (LBD) and stabilize the agonist-bound conformation, thereby slowing receptor desensitization and/or deactivation. Here we describe the synthesis and pharmacological testing at GluA2 of a new generation of 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides. The most potent modulator 3 in complex with GluA2-LBD-L483Y-N754S was subjected to structural analysis by X-ray crystallography, and the thermodynamics of binding was studied by isothermal titration calorimetry. Compound 3 binds to GluA2-LBD-L483Y-N754S with a Kd of 0.35 μM (ΔH = -7.5 kcal/mol and -TΔS = -1.3 kcal/mol). This is the first time that submicromolar binding affinity has been achieved for this type of positive allosteric modulator. The major structural factor increasing the binding affinity of 3 seems to be interactions between the cyclopropyl group of 3 and the backbone of Phe495 and Met496.

AB - Positive allosteric modulators of ionotropic glutamate receptors are potential compounds for treatment of cognitive disorders, e.g., Alzheimer's disease. The modulators bind within the dimer interface of the ligand-binding domain (LBD) and stabilize the agonist-bound conformation, thereby slowing receptor desensitization and/or deactivation. Here we describe the synthesis and pharmacological testing at GluA2 of a new generation of 3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxides. The most potent modulator 3 in complex with GluA2-LBD-L483Y-N754S was subjected to structural analysis by X-ray crystallography, and the thermodynamics of binding was studied by isothermal titration calorimetry. Compound 3 binds to GluA2-LBD-L483Y-N754S with a Kd of 0.35 μM (ΔH = -7.5 kcal/mol and -TΔS = -1.3 kcal/mol). This is the first time that submicromolar binding affinity has been achieved for this type of positive allosteric modulator. The major structural factor increasing the binding affinity of 3 seems to be interactions between the cyclopropyl group of 3 and the backbone of Phe495 and Met496.

KW - Allosteric Regulation

KW - Animals

KW - Benzothiadiazines

KW - Calorimetry

KW - Crystallography, X-Ray

KW - Cyclic S-Oxides

KW - Dose-Response Relationship, Drug

KW - Models, Molecular

KW - Molecular Structure

KW - Neurons

KW - Rats

KW - Receptors, AMPA

KW - Structure-Activity Relationship

KW - Thermodynamics

U2 - 10.1021/jm4012092

DO - 10.1021/jm4012092

M3 - Journal article

C2 - 24131202

VL - 56

SP - 8736

EP - 8745

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

SN - 0022-2623

IS - 21

ER -

ID: 107359213