Article (Scientific journals)
Positive Allosteric Modulators of 2-Amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic Acid Receptors Belonging to 4-Cyclopropyl-3,4-dihydro-2H-1,2,4-pyridothiadiazine Dioxides and Diversely Chloro-Substituted 4-Cyclopropyl-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-Dioxides
Francotte, Pierre; Nørholm, Ann-Beth; Deva, Taru et al.
2014In Journal of Medicinal Chemistry, 57 (22), p. 9539-9553
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Abstract :
[en] Two 4-ethyl-substituted pyridothiadiazine dioxides belonging to α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor positive allosteric modulators were cocrystallized with the GluA2 ligand binding domain in order to decipher the impact of the position of the nitrogen atom on their binding mode at the AMPA receptors. The latter was found to be very similar to that of previously described benzothiadiazine-type AMPA receptor modulators. The affinity of the two compounds for the receptor was determined by isothermal titration calorimetry. Accordingly, the synthesis and biological evaluation of novel 4-cyclopropyl-substituted pyridothiadiazine dioxides was performed and completed with the synthesis of the corresponding chloro-substituted 4-cyclopropyl-3,4-dihydro-2H-benzothiadiazine 1,1-dioxides. The “8-aza” compound 32 was found to be the most potent pyridothiadiazine-type AMPA receptor potentiator in vitro, whereas the 7-chloro-substituted compound 36c emerged as the most promising benzothiadiazine dioxide. Due to proper drug-likeness and low in vivo acute toxicity in mice, 36c was chosen for a more complete preclinical evaluation. The compound was able to easily cross the blood–brain barrier. In an in vivo object recognition test with CD1 mice, oral administration of 36c was found to significantly improve cognition performance at doses as low as 1 mg/kg.
Disciplines :
Pharmacy, pharmacology & toxicology
Chemistry
Author, co-author :
Francotte, Pierre   ;  Université de Liège > Département de pharmacie > Chimie pharmaceutique
Nørholm, Ann-Beth 
Deva, Taru
Olsen, Lars
Frydenvang, Karla
Goffin, Eric ;  Université de Liège > Département de pharmacie > Chimie pharmaceutique
Fraikin, Pierre
De Tullio, Pascal ;  Université de Liège > Département de pharmacie > Chimie pharmaceutique
Challal, Sylvie
Thomas, Jean-Yves
Iop, Fabrice
Louis, Caroline
Botez-Pop, Iuliana
Lestage, Pierre
Danober, Laurence
Kastrup, Jette S.
Pirotte, Bernard ;  Université de Liège > Département de pharmacie > Chimie pharmaceutique
More authors (7 more) Less
 These authors have contributed equally to this work.
Language :
English
Title :
Positive Allosteric Modulators of 2-Amino-3-(3-hydroxy-5-methylisoxazol-4-yl)propionic Acid Receptors Belonging to 4-Cyclopropyl-3,4-dihydro-2H-1,2,4-pyridothiadiazine Dioxides and Diversely Chloro-Substituted 4-Cyclopropyl-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-Dioxides
Publication date :
06 November 2014
Journal title :
Journal of Medicinal Chemistry
ISSN :
0022-2623
eISSN :
1520-4804
Publisher :
American Chemical Society, Washington, United States - District of Columbia
Volume :
57
Issue :
22
Pages :
9539-9553
Peer reviewed :
Peer Reviewed verified by ORBi
Available on ORBi :
since 10 June 2015

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