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

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

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 languageEnglish
JournalJournal of Medicinal Chemistry
Issue number21
Pages (from-to)8736-45
Number of pages10
Publication statusPublished - 14 Nov 2013

    Research areas

  • 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

ID: 107359213