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

Ann-Beth Nørholm; Pierre Francotte; Lars Olsen; Christian Krintel; Karla Frydenvang; Eric Goffin; Sylvie Challal; Laurence Danober; Iuliana Botez-Pop; Pierre Lestage; Bernard Pirotte; Jette S Kastrup

doi:10.1021/jm4012092

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

Ann-Beth Nørholm, Pierre Francotte, Lars Olsen, Christian Krintel, Karla Frydenvang, Eric Goffin, Sylvie Challal, Laurence Danober, Iuliana Botez-Pop, Pierre Lestage, Bernard Pirotte, Jette S Kastrup

21 Citations (Scopus)

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.

Original language	English
Journal	Journal of Medicinal Chemistry
Volume	56
Issue number	21
Pages (from-to)	8736-45
Number of pages	10
ISSN	0022-2623
DOIs	https://doi.org/10.1021/jm4012092
Publication status	Published - 14 Nov 2013

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

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10.1021/jm4012092

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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, 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

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 et al.

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

Research output: Contribution to journal › Journal article › Research

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

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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.",

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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

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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

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DO - 10.1021/jm4012092

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C2 - 24131202

SN - 0022-2623

VL - 56

SP - 8736

EP - 8745

JO - Journal of Medicinal Chemistry

JF - Journal of Medicinal Chemistry

IS - 21

ER -

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

Keywords

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