4n07 › Citations

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 AB, Francotte P, Olsen L, Krintel C, Frydenvang K, Goffin E, Challal S, Danober L, Botez-Pop I, Lestage P, Pirotte B, Kastrup JS
J Med Chem 56 8736-45 (2013)
Cited: 12 times
EuropePMC logo PMID: 24131202

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.

Articles - 4n07 mentioned but not cited (1)

  1. Enthalpy-Entropy Compensation in the Binding of Modulators at Ionotropic Glutamate Receptor GluA2. Krintel C, Francotte P, Pickering DS, Juknaitė L, Pøhlsgaard J, Olsen L, Frydenvang K, Goffin E, Pirotte B, Kastrup JS. Biophys J 110 2397-2406 (2016)


Reviews citing this publication (4)

  1. Structure, Function, and Pharmacology of Glutamate Receptor Ion Channels. Hansen KB, Wollmuth LP, Bowie D, Furukawa H, Menniti FS, Sobolevsky AI, Swanson GT, Swanger SA, Greger IH, Nakagawa T, McBain CJ, Jayaraman V, Low CM, Dell'Acqua ML, Diamond JS, Camp CR, Perszyk RE, Yuan H, Traynelis SF. Pharmacol Rev 73 298-487 (2021)
  2. AMPA receptor potentiators: from drug design to cognitive enhancement. Partin KM. Curr Opin Pharmacol 20 46-53 (2015)
  3. Radicals and Sulfur Dioxide: A Versatile Combination for the Construction of Sulfonyl-Containing Molecules. Hofman K, Liu NW, Manolikakes G. Chemistry 24 11852-11863 (2018)
  4. AMPA receptor-positive allosteric modulators for the treatment of schizophrenia: an overview of recent patent applications. Ward SE, Pennicott LE, Beswick P. Future Med Chem 7 473-491 (2015)

Articles citing this publication (7)

  1. 7-Phenoxy-Substituted 3,4-Dihydro-2H-1,2,4-benzothiadiazine 1,1-Dioxides as Positive Allosteric Modulators of α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptors with Nanomolar Potency. Goffin E, Drapier T, Larsen AP, Geubelle P, Ptak CP, Laulumaa S, Rovinskaja K, Gilissen J, Tullio P, Olsen L, Frydenvang K, Pirotte B, Hanson J, Oswald RE, Kastrup JS, Francotte P. J Med Chem 61 251-264 (2018)
  2. Allosteric Modulation of Ionotropic Glutamate Receptors: An Outlook on New Therapeutic Approaches To Treat Central Nervous System Disorders. Brogi S, Campiani G, Brindisi M, Butini S. ACS Med Chem Lett 10 228-236 (2019)
  3. A quantum biochemistry investigation of willardiine partial agonism in AMPA receptors. Lima Neto JX, Fulco UL, Albuquerque EL, Corso G, Bezerra EM, Caetano EW, da Costa RF, Freire VN. Phys Chem Chem Phys 17 13092-13103 (2015)
  4. Identification and Structure-Function Study of Positive Allosteric Modulators of Kainate Receptors. Larsen AP, Fièvre S, Frydenvang K, Francotte P, Pirotte B, Kastrup JS, Mulle C. Mol Pharmacol 91 576-585 (2017)
  5. Crystal Structures of Potent Dimeric Positive Allosteric Modulators at the Ligand-Binding Domain of the GluA2 Receptor. Laulumaa S, Hansen KV, Masternak M, Drapier T, Francotte P, Pirotte B, Frydenvang K, Kastrup JS. ACS Med Chem Lett 10 243-247 (2019)
  6. Functionalized Fluorescent Nanodiamonds for Simultaneous Drug Delivery and Quantum Sensing in HeLa Cells. Tian Y, Nusantara AC, Hamoh T, Mzyk A, Tian X, Perona Martinez F, Li R, Permentier HP, Schirhagl R. ACS Appl Mater Interfaces 14 39265-39273 (2022)
  7. Fully Automated Synthesis and Evaluation of [18 F]BPAM121: Potential of an AMPA Receptor Positive Allosteric Modulator as PET Radiotracer. Manos-Turvey A, Becker G, Francotte P, Serrano ME, Luxen A, Pirotte B, Plenevaux A, Lemaire C. ChemMedChem 14 788-795 (2019)


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