TY - JOUR
T1 - 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
AU - Etsè, Koffi Sénam
AU - Dorosz, Jerzy
AU - McLain Christensen, Katrine
AU - Thomas, Jean Yves
AU - Botez Pop, Iuliana
AU - Goffin, Eric
AU - Colson, Thomas
AU - Lestage, Pierre
AU - Danober, Laurence
AU - Pirotte, Bernard
AU - Kastrup, Jette Sandholm
AU - Francotte, Pierre
N1 - Funding Information:
We acknowledge funding from the Danish Council for Independent Research—Medical Sciences and Danscatt (J.D., J.S.K.) and the Léon Fredericq Foundation (T.C.).
Publisher Copyright:
© 2021 American Chemical Society.
PY - 2021
Y1 - 2021
N2 - On the basis of the activity of 1,2,4-benzothiadiazine 1,1-dioxides as positive allosteric modulators of AMPA receptors, thiochroman 1,1-dioxides were designed applying the isosteric replacement concept. The new compounds expressed strong modulatory activity on AMPA receptors in vitro, although lower than their corresponding benzothiadiazine analogues. The pharmacokinetic profile of three thiochroman 1,1-dioxides (12a, 12b, 12e) was examined in vivo after oral administration, showing that these compounds freely cross the blood-brain barrier. Structural analysis was achieved using X-ray crystallography after cocrystallization of the racemic compound 12b in complex with the ligand-binding domain of GluA2 (L504Y/N775S). Interestingly, both enantiomers of 12b were found to interact with the GluA2 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 fingerprint) and compared to those of 4. Taken together, these data explain the lower affinity on AMPA receptors of thiochroman 1,1-dioxides compared to their corresponding 1,2,4-benzothiadiazine 1,1-dioxides.
AB - On the basis of the activity of 1,2,4-benzothiadiazine 1,1-dioxides as positive allosteric modulators of AMPA receptors, thiochroman 1,1-dioxides were designed applying the isosteric replacement concept. The new compounds expressed strong modulatory activity on AMPA receptors in vitro, although lower than their corresponding benzothiadiazine analogues. The pharmacokinetic profile of three thiochroman 1,1-dioxides (12a, 12b, 12e) was examined in vivo after oral administration, showing that these compounds freely cross the blood-brain barrier. Structural analysis was achieved using X-ray crystallography after cocrystallization of the racemic compound 12b in complex with the ligand-binding domain of GluA2 (L504Y/N775S). Interestingly, both enantiomers of 12b were found to interact with the GluA2 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 fingerprint) and compared to those of 4. Taken together, these data explain the lower affinity on AMPA receptors of thiochroman 1,1-dioxides compared to their corresponding 1,2,4-benzothiadiazine 1,1-dioxides.
KW - 1,2,4-Benzothiadiazine 1,1-dioxide
KW - AMPA receptor
KW - Hirshfeld surface analysis
KW - Ionotropic glutamate receptors
KW - Positive allosteric modulator
KW - Thiochroman 1,1-dioxide
KW - X-ray crystallography
U2 - 10.1021/acschemneuro.1c00255
DO - 10.1021/acschemneuro.1c00255
M3 - Journal article
C2 - 34242002
AN - SCOPUS:85111214875
VL - 12
SP - 2679
EP - 2692
JO - ACS Chemical Neuroscience
JF - ACS Chemical Neuroscience
SN - 1948-7193
IS - 14
ER -