Koffi Sénam Etsè, Jerzy Dorosz, Katrine McLain Christensen, Jean-Yves Thomas, Iuliana Botez Pop, Eric Goffin, Thomas Colson, Pierre Lestage, Laurence Danober, Bernard Pirotte, Jette Sandholm Kastrup, Pierre Francotte.This article is cited by 26 publications. 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. This is the first time that submicromolar binding affinity has been achieved for this type of positive allosteric modulator. Compound 3 binds to GluA2-LBD-L483Y-N754S with a K d of 0.35 μM (Δ H = −7.5 kcal/mol and − TΔ S = −1.3 kcal/mol). 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. Here we describe the synthesis and pharmacological testing at GluA2 of a new generation of 3,4-dihydro-2 H-1,2,4-benzothiadiazine 1,1-dioxides. 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. Positive allosteric modulators of ionotropic glutamate receptors are potential compounds for treatment of cognitive disorders, e.g., Alzheimer’s disease.
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