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
[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
scite shows how a scientific paper has been cited by providing the context of the citation, a classification describing whether it supports, mentions, or contrasts the cited claim, and a label indicating in which section the citation was made.
Bibliography
Traynelis, S. F.; Wollmuth, L. P.; McBain, C. J.; Menniti, F. S.; Vance, K. M.; Ogden, K. K.; Hansen, K. B.; Yuan, H.; Myers, S. J.; Dingledine, R. Glutamate receptor ion channels: structure, regulation, and function Pharmacol. Rev. 2010, 62, 405-496
Adler, L. A.; Kroon, R. A.; Stein, M.; Shahid, M.; Tarazi, F. I.; Szegedi, A.; Schipper, J.; Cazorla, P. A translational approach to evaluate the efficacy and safety of the novel AMPA receptor positive allosteric modulator Org 26576 in adult attention-deficit/hyperactivity disorder Biol. Psychiatry 2012, 72, 971-977
Lynch, G. AMPA receptor modulators as cognitive enhancers Curr. Opin. Pharmacol. 2004, 4, 4-11
Goff, D. C.; Leahy, L.; Berman, I.; Posever, T.; Herz, L.; Leon, A. C.; Johnson, S. A.; Lynch, G. A placebo-controlled pilot study of the ampakine CX516 added to clozapine in schizophrenia J. Clin. Psychopharmacol. 2001, 21, 484-487
Sobolevsky, A. I.; Rosconi, M. P.; Gouaux, E. X-ray structure, symmetry and mechanism of an AMPA-subtype glutamate receptor Nature 2009, 462, 745-756
Armstrong, N.; Gouaux, E. Mechanisms for activation and antagonism of an AMPA-sensitive glutamate receptor: crystal structures of the GluR2 ligand binding core Neuron 2000, 28, 165-181
Sun, Y.; Olson, R.; Horning, M.; Armstrong, N.; Mayer, M.; Gouaux, E. Mechanism of glutamate receptor desensitization Nature 2002, 417, 245-253
Jin, R.; Clark, S.; Weeks, A. M.; Dudman, J. T.; Gouaux, E.; Partin, K. M. Mechanism of positive allosteric modulators acting on AMPA receptors J. Neurosci. 2005, 25, 9027-9036
Pirotte, B.; Podona, T.; Diouf, O.; de Tullio, P.; Lebrun, P.; Dupont, L.; Somers, F.; Delarge, J.; Morain, P.; Lestage, P.; Lepagnol, J.; Spedding, M. 4 H -1,2,4-Pyridothiadiazine 1,1-dioxides and 2,3-dihydro-4 H -1,2, 4-pyridothiadiazine 1,1-dioxides chemically related to diazoxide and cyclothiazide as powerful positive allosteric modulators of (R / S)-2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid receptors: design, synthesis, pharmacology, and structure-activity relationships J. Med. Chem. 1998, 41, 2946-2959
Francotte, P.; de Tullio, P.; Goffin, E.; Dintilhac, G.; Graindorge, E.; Fraikin, P.; Lestage, P.; Danober, L.; Thomas, J. Y.; Caignard, D. H.; Pirotte, B. Design, synthesis, and pharmacology of novel 7-substituted 3,4-dihydro-2 H -1,2,4-benzothiadiazine 1,1-dioxides as positive allosteric modulators of AMPA receptors J. Med. Chem. 2007, 50, 3153-7315
Francotte, P.; de Tullio, P.; Podona, T.; Diouf, O.; Fraikin, P.; Lestage, P.; Danober, L.; Thomas, J. Y.; Caignard, D. H.; Pirotte, B. Synthesis and pharmacological evaluation of a second generation of pyridothiadiazine 1,1-dioxides acting as AMPA potentiators Bioorg. Med. Chem. 2008, 16, 9948-9956
Francotte, P.; Goffin, E.; Fraikin, P.; Lestage, P.; Van Heugen, J. C.; Gillotin, F.; Danober, L.; Thomas, J. Y.; Chiap, P.; Caignard, D. H.; Pirotte, B.; de Tullio, P. New fluorinated 1,2,4-benzothiadiazine 1,1-dioxides: discovery of an orally active cognitive enhancer acting through potentiation of the 2-amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic acid receptors J. Med. Chem. 2010, 53, 1700-1711
Krintel, C.; Frydenvang, K.; Olsen, L.; Kristensen, M. T.; de Barrios, O.; Naur, P.; Francotte, P.; Pirotte, B.; Gajhede, M.; Kastrup, J. S. Thermodynamics and structural analysis of positive allosteric modulation of the ionotropic glutamate receptor GluA2 Biochem. J. 2012, 441, 173-178
Meerwein, H.; Dittmar, G.; Gollner, R.; Hafner, K.; Mensch, F.; Steinfort, O. Aromatic diazo compounds. II. Preparation of aromatic sulfonyl chlorides, a new modification of the Sandmeyer reaction Chem. Ber. 1957, 90, 841-852
Partin, K. M.; Fleck, M. W.; Mayer, M. L. AMPA receptor flip/flop mutants affecting deactivation, desensitization, and modulation by cyclothiazide, aniracetam, and thiocyanate J. Neurosci. 1996, 16, 6634-6647
Pøhlsgaard, J.; Frydenvang, K.; Madsen, U.; Kastrup, J. S. Lessons from more than 80 structures of the GluA2 ligand-binding domain in complex with agonists, antagonists and allosteric modulators Neuropharmacology 2011, 60, 135-150
Galano, A.; Alvarez-Idaboy, J.; Vivier-Bunge, A. Non-alkane behavior of cyclopropane and its derivatives: characterization of unconventional hydrogen bond interactions Theor. Chem. Acc. 2007, 118, 597-606
Wheeler, S. E.; Houk, K. N. Substituent effects in the benzene dimer are due to direct interactions of the substituents with the unsubstituted benzene J. Am. Chem. Soc. 2008, 130, 10854-10855
Ahmed, A. H.; Ptak, C. P.; Oswald, R. E. Molecular mechanism of flop selectivity and subsite recognition for an AMPA receptor allosteric modulator: structures of GluA2 and GluA3 in complexes with PEPA Biochemistry 2010, 49, 2843-2850
Winn, M. D.; Ballard, C. C.; Cowtan, K. D.; Dodson, E. J.; Emsley, P.; Evans, P. R.; Keegan, R. M.; Krissinel, E. B.; Leslie, A. G. W.; McCoy, A.; McNicholas, S. J.; Murshudov, G. N.; Pannu, N. S.; Potterton, E. A.; Powell, H. R.; Read, R. J.; Vagin, A.; Wilson, K. S. Overview of the CCP4 suite and current developments Acta Crystallogr., Sect. D: Biol. Crystallogr. 2011, 67, 235-242
McCoy, A. J.; Grosse-Kunstleve, R. W.; Adams, P. D.; Winn, M. D.; Storoni, L. C.; Read, R. J. Phaser crystallographic software J. Appl. Crystallogr. 2007, 40, 658-674
Cohen, S. X.; Ben Jelloul, M.; Long, F.; Vagin, A.; Knipscheer, P.; Lebbink, J.; Sixma, T. K.; Lamzin, V. S.; Murshudov, G. N.; Perrakis, A. ARP/wARP and molecular replacement: the next generation Acta Crystallogr., Sect. D: Biol. Crystallogr. 2008, 64, 49-60
Emsley, P.; Lohkamp, B.; Scott, W. G.; Cowtan, K. Features and development of Coot Acta Crystallogr., Sect. D: Biol. Crystallogr. 2010, 66, 486-501
Schuettelkopf, A. W.; van Aalten, D. M. F. PRODRG-a tool for high-throughput crystallography of protein-ligand complexes Acta Crystallogr., Sect. D: Biol. Crystallogr. 2004, 60, 1355-1363
Moriarty, N. W.; Grosse-Kunstleve, R. W.; Adams, P. D. Electronic Ligand Builder and Optimization Workbench (eLBOW): a tool for ligand coordinate and restraint generation Acta Crystallogr., Sect. D: Biol. Crystallogr. 2009, 65, 1074-1080
Adams, P. D.; Afonine, P. V.; Bunkoczi, G.; Chen, V. B.; Davis, I. W.; Echols, N.; Headd, J. J.; Hung, L. W.; Kapral, G. J.; Grosse-Kunstleve, R. W.; McCoy, A. J.; Moriarty, N. W.; Oeffner, R.; Read, R. J.; Richardson, D. C.; Richardson, J. S.; Terwilliger, T. C.; Zwart, P. H. PHENIX: a comprehensive Python-based system for macromolecular structure solution Acta Crystallogr., Sect. D: Biol. Crystallogr. 2010, 66, 213-221
Hayward, S.; Lee, R. A. Improvements in the analysis of domain motions in proteins from conformational change: DynDom version 1.50 J. Mol. Graphics Modell. 2002, 21, 181-183
Wiseman, T.; Williston, S.; Brandts, J. F.; Lin, L. N. Rapid measurement of binding constants and heats of binding using a new titration calorimeter Anal. Biochem. 1989, 179, 131-137
Laskowski, R. A.; Macarthur, M. W.; Moss, D. S.; Thornton, J. M. PROCHECK-a program to check the stereochemical quality of protein structures J. Appl. Crystallogr. 1993, 26, 283-291
Similar publications
Sorry the service is unavailable at the moment. Please try again later.
This website uses cookies to improve user experience. Read more
Save & Close
Accept all
Decline all
Show detailsHide details
Cookie declaration
About cookies
Strictly necessary
Performance
Strictly necessary cookies allow core website functionality such as user login and account management. The website cannot be used properly without strictly necessary cookies.
This cookie is used by Cookie-Script.com service to remember visitor cookie consent preferences. It is necessary for Cookie-Script.com cookie banner to work properly.
Performance cookies are used to see how visitors use the website, eg. analytics cookies. Those cookies cannot be used to directly identify a certain visitor.
Used to store the attribution information, the referrer initially used to visit the website
Cookies are small text files that are placed on your computer by websites that you visit. Websites use cookies to help users navigate efficiently and perform certain functions. Cookies that are required for the website to operate properly are allowed to be set without your permission. All other cookies need to be approved before they can be set in the browser.
You can change your consent to cookie usage at any time on our Privacy Policy page.