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.
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.
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen , Universitetsparken 2, DK-2100 Copenhagen, Denmark.
authors.forename: Ann-Beth
authors.initials: AB
authors.lastname: Nørholm
authors.forename: Pierre
authors.initials: P
authors.lastname: Francotte
authors.forename: Lars
authors.initials: L
authors.lastname: Olsen
authors.forename: Christian
authors.initials: C
authors.lastname: Krintel
authors.forename: Karla
authors.initials: K
authors.lastname: Frydenvang
authors.forename: Eric
authors.initials: E
authors.lastname: Goffin
authors.forename: Sylvie
authors.initials: S
authors.lastname: Challal
authors.forename: Laurence
authors.initials: L
authors.lastname: Danober
authors.forename: Iuliana
authors.initials: I
authors.lastname: Botez-Pop
authors.forename: Pierre
authors.initials: P
authors.lastname: Lestage
authors.forename: Bernard
authors.initials: B
authors.lastname: Pirotte
authors.forename: Jette S
authors.initials: JS
authors.lastname: Kastrup
mesh_terms: D000494:Allosteric Regulation / Q000187:drug effects*; D000818:Animals; D001581:Benzothiadiazines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D002151:Calorimetry; D018360:Crystallography, X-Ray; D003499:Cyclic S-Oxides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D008958:Models, Molecular; D015394:Molecular Structure; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D051381:Rats; D018091:Receptors, AMPA / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013816:Thermodynamics
chemical_list: C587006:4-cyclopropyl-7-fluoro-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide; D001581:Benzothiadiazines; D003499:Cyclic S-Oxides; D018091:Receptors, AMPA; C104722:glutamate receptor ionotropic, AMPA 2