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
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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 journal › Journal article › Research
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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