دورية أكاديمية
Exploring thienothiadiazine dioxides as isosteric analogues of benzo-and pyridothiadiazine dioxides in the search of new AMPA and kainate receptor positive allosteric modulators
العنوان: | 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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المؤلفون: | 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, Frydenvang, Karla, Danober, Laurence, Skov Kristensen, Anders, Sandholm Kastrup, Jette, Pirotte, Bernard |
المصدر: | European Journal of Medicinal Chemistry, 264, 116036 (2023-12-09) |
بيانات النشر: | Elsevier BV, 2023. |
سنة النشر: | 2023 |
مصطلحات موضوعية: | Ionotropic glutamate receptors Positive allosteric modulators thieno[3, 2-e]-1, 2, 4-thiadiazine 1, 1-dioxides 1, 4-Benzothiadiazine 1, 1-dioxides X-ray crystallography Calcium-sensitive fluorescence-based assay, Organic Chemistry, Drug Discovery, Pharmacology, General Medicine, Human health sciences, Pharmacy, pharmacology & toxicology, Physical, chemical, mathematical & earth Sciences, Chemistry, Sciences de la santé humaine, Pharmacie, pharmacologie & toxicologie, Physique, chimie, mathématiques & sciences de la terre, Chimie |
الوصف: | 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. |
نوع الوثيقة: | journal article http://purl.org/coar/resource_type/c_6501 article peer reviewed |
اللغة: | English |
Relation: | https://api.elsevier.com/content/article/PII:S0223523423010036?httpAccept=text/xml; urn:issn:0223-5234; urn:issn:1768-3254 |
DOI: | 10.1016/j.ejmech.2023.116036 |
URL الوصول: | https://orbi.uliege.be/handle/2268/312961 |
حقوق: | open access http://purl.org/coar/access_right/c_abf2 info:eu-repo/semantics/openAccess |
رقم الأكسشن: | edsorb.312961 |
قاعدة البيانات: | ORBi |
DOI: | 10.1016/j.ejmech.2023.116036 |
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