Article (Scientific journals)
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.
2013In Journal of Medicinal Chemistry, 56 (21), p. 8736–8745
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Abstract :
[en] 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.
Disciplines :
Pharmacy, pharmacology & toxicology
Chemistry
Author, co-author :
Nørholm, Ann-Beth
Francotte, Pierre  ;  Université de Liège - ULiège > Département de pharmacie > Chimie pharmaceutique
Olsen, Lars
Krintel, Christian
Frydenvang, Karla
Goffin, Eric ;  Université de Liège - ULiège > Département de pharmacie > Chimie pharmaceutique
Challal, Sylvie
Danober, Laurence
Botez-Pop, Iuliana
Lestage, Pierre
Pirotte, Bernard ;  Université de Liège - ULiège > Département de pharmacie > Chimie pharmaceutique
Kastrup, Jette S.
Language :
English
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
Publication date :
16 October 2013
Journal title :
Journal of Medicinal Chemistry
ISSN :
0022-2623
eISSN :
1520-4804
Publisher :
American Chemical Society, Washington, United States - District of Columbia
Volume :
56
Issue :
21
Pages :
8736–8745
Peer reviewed :
Peer Reviewed verified by ORBi
Available on ORBi :
since 25 November 2013

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