Exploring thienothiadiazine dioxides as isosteric analogues of benzo- and pyridothiadiazine dioxides in the search of new AMPA and kainate receptor positive allosteric modulators
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Exploring thienothiadiazine dioxides as isosteric analogues of benzo- and pyridothiadiazine dioxides in the search of new AMPA and kainate receptor positive allosteric modulators. / Francotte, Pierre; Bay, Yasmin; Goffin, Eric; Colson, Thomas; Lesenfants, Cindy; Dorosz, Jerzy; Laulumaa, Saara; Fraikin, Pierre; de Tullio, Pascal; Beaufour, Caroline; Botez, Iuliana; Pickering, Darryl S.; Frydenvang, Karla; Danober, Laurence; Kristensen, Anders Skov; Kastrup, Jette Sandholm; Pirotte, Bernard.
I: European Journal of Medicinal Chemistry, Bind 264, 116036, 2024.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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TY - JOUR
T1 - Exploring thienothiadiazine dioxides as isosteric analogues of benzo- and pyridothiadiazine dioxides in the search of new AMPA and kainate receptor positive allosteric modulators
AU - Francotte, Pierre
AU - Bay, Yasmin
AU - Goffin, Eric
AU - Colson, Thomas
AU - Lesenfants, Cindy
AU - Dorosz, Jerzy
AU - Laulumaa, Saara
AU - Fraikin, Pierre
AU - de Tullio, Pascal
AU - Beaufour, Caroline
AU - Botez, Iuliana
AU - Pickering, Darryl S.
AU - Frydenvang, Karla
AU - Danober, Laurence
AU - Kristensen, Anders Skov
AU - Kastrup, Jette Sandholm
AU - Pirotte, Bernard
N1 - Publisher Copyright: © 2023 Elsevier Masson SAS
PY - 2024
Y1 - 2024
N2 - The synthesis and biological evaluation on AMPA and kainate receptors of new examples of 3,4-dihydro-2H-1,2,4-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxides is described. The introduction of a cyclopropyl chain instead of an ethyl chain at the 4-position of the thiadiazine ring was found to dramatically improve the potentiator activity on AMPA receptors, with compound 32 (BPAM395) expressing in vitro activity on AMPARs (EC2x = 0.24 μM) close to that of the reference 4-cyclopropyl-substituted benzothiadiazine dioxide 10 (BPAM344). Interestingly, the 4-allyl-substituted thienothiadiazine dioxide 27 (BPAM307) emerged as the most promising compound on kainate receptors being a more effective potentiator than the 4-cyclopropyl-substituted thienothiadiazine dioxide 32 and supporting the view that the 4-allyl substitution of the thiadiazine ring could be more favorable than the 4-cyclopropyl substitution to induce marked activity on kainate receptors versus AMPA receptors. The thieno-analogue 36 (BPAM279) of the clinically tested S18986 (11) was selected for in vivo evaluation in mice as a cognitive enhancer due to a safer profile than 32 after massive per os drug administration. Compound 36 was found to increase the cognition performance in mice at low doses (1 mg/kg) per os suggesting that the compound was well absorbed after oral administration and able to reach the central nervous system. Finally, compound 32 was selected for co-crystallization with the GluA2-LBD (L504Y,N775S) and glutamate to examine the binding mode of thienothiadiazine dioxides within the allosteric binding site of the AMPA receptor. At the allosteric site, this compound established similar interactions as the previously reported BTD-type AMPA receptor modulators.
AB - The synthesis and biological evaluation on AMPA and kainate receptors of new examples of 3,4-dihydro-2H-1,2,4-thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxides is described. The introduction of a cyclopropyl chain instead of an ethyl chain at the 4-position of the thiadiazine ring was found to dramatically improve the potentiator activity on AMPA receptors, with compound 32 (BPAM395) expressing in vitro activity on AMPARs (EC2x = 0.24 μM) close to that of the reference 4-cyclopropyl-substituted benzothiadiazine dioxide 10 (BPAM344). Interestingly, the 4-allyl-substituted thienothiadiazine dioxide 27 (BPAM307) emerged as the most promising compound on kainate receptors being a more effective potentiator than the 4-cyclopropyl-substituted thienothiadiazine dioxide 32 and supporting the view that the 4-allyl substitution of the thiadiazine ring could be more favorable than the 4-cyclopropyl substitution to induce marked activity on kainate receptors versus AMPA receptors. The thieno-analogue 36 (BPAM279) of the clinically tested S18986 (11) was selected for in vivo evaluation in mice as a cognitive enhancer due to a safer profile than 32 after massive per os drug administration. Compound 36 was found to increase the cognition performance in mice at low doses (1 mg/kg) per os suggesting that the compound was well absorbed after oral administration and able to reach the central nervous system. Finally, compound 32 was selected for co-crystallization with the GluA2-LBD (L504Y,N775S) and glutamate to examine the binding mode of thienothiadiazine dioxides within the allosteric binding site of the AMPA receptor. At the allosteric site, this compound established similar interactions as the previously reported BTD-type AMPA receptor modulators.
KW - 1,2,4-Benzothiadiazine 1,1-dioxides
KW - Calcium-sensitive fluorescence-based assay
KW - Ionotropic glutamate receptors
KW - Positive allosteric modulators
KW - thieno[3,2-e]-1,2,4-thiadiazine 1,1-dioxides
KW - X-ray crystallography
U2 - 10.1016/j.ejmech.2023.116036
DO - 10.1016/j.ejmech.2023.116036
M3 - Journal article
C2 - 38101041
AN - SCOPUS:85179988517
VL - 264
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
SN - 0223-5234
M1 - 116036
ER -
ID: 378767723