Article (Scientific journals)
Development of Thiochroman Dioxide Analogues of Benzothiadiazine Dioxides as New Positive Allosteric Modulators of α-Amino-3- hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptors
Etse, Koffi Senam; Dorosz, Jerzy; Mc Lain Christensen et al.
2021In ACS Chemical Neurosciences, 12 (14), p. 2679-2692
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Abstract :
[en] Based on the activity of 1,2,4-benzothiadiazine 1,1-dioxides as AMPAR-PAMs, thiochroman 1,1-dioxides were designed apply- ing the isosteric replacement concept. The new compounds expressed a strong modulatory activity on AMPARs in vitro, although lower than their corresponding benzothiadiazine analogues. The pharmacokinetic profile of three thiochroman 1,1-dioxides (12a, 12b, 12e) was exam- ined in vivo after oral administration, showing that these compounds freely cross the blood-brain barrier. Structural analysis was achieved using X-ray crystallography after cocrystallisation of the racemic compound 12b in complex with GluA2-LBD (L504Y/N775S). Interestingly, both enantiomers of 12b were found to interact with the GluA2-LBD dimer interface, almost identically to its benzothiadiazine analogue, BPAM344 (4). The interactions of the two enantiomers in the cocrystal were further analyzed (mapping Hirshfeld surfaces and 2D finger- print) and compared to those of 4. Taken together, these data explain the lower affinity on AMPARs of thiochroman 1,1-dioxides compared to their corresponding 1,2,4-benzothiadiazine 1,1-dioxides.
Research center :
CIRM - Centre Interdisciplinaire de Recherche sur le Médicament - ULiège
Disciplines :
Pharmacy, pharmacology & toxicology
Author, co-author :
Etse, Koffi Senam ;  Université de Liège - ULiège > Département de pharmacie > Chimie analytique
Dorosz, Jerzy
Mc Lain Christensen
Thomas, Jean-Yves
Botez Pop, Iuliana
Goffin, Eric
Colson, Thomas  ;  Université de Liège - ULiège > Master sc. pharma., à fin.
Lestage, Pierre
Danober, Laurence
Pirotte, Bernard ;  Université de Liège - ULiège > Département de pharmacie > Chimie pharmaceutique
Sandholm Katrup, Jette
Francotte, Pierre  ;  Université de Liège - ULiège > Département de pharmacie > Chimie pharmaceutique
Language :
English
Title :
Development of Thiochroman Dioxide Analogues of Benzothiadiazine Dioxides as New Positive Allosteric Modulators of α-Amino-3- hydroxy-5-methyl-4-isoxazolepropionic Acid (AMPA) Receptors
Publication date :
09 July 2021
Journal title :
ACS Chemical Neurosciences
ISSN :
1948-7193
Publisher :
American Chemical Society, United States - District of Columbia
Volume :
12
Issue :
14
Pages :
2679-2692
Peer reviewed :
Peer Reviewed verified by ORBi
Funders :
Fonds Léon Fredericq [BE]
Available on ORBi :
since 25 June 2021

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