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 -