5-Arylbenzothiadiazine Type Compounds as Positive Allosteric Modulators of AMPA/Kainate Receptors
详细信息 查看全文
- 作者：Umberto M. Battisti ; Krzysztof Jozwiak ; Giuseppe Cannazza ; Giulia Puia ; Gabriella Stocca ; Daniela Braghiroli ; Carlo Parenti ; Livio Brasili ; Marina M. Carrozzo ; Cinzia Citti ; Luigino Troisi
- 刊名：ACS Medicinal Chemistry Letters
- 出版年：2012
- 出版时间：January 12, 2012
- 年：2012
- 卷：3
- 期：1
- 页码：25-29
- 全文大小：283K
- 年卷期：v.3,no.1(January 12, 2012)
- ISSN：1948-5875
文摘
The potential therapeutic benefit of compounds able to activate AMPA receptors (AMPAr) has led to the search for new AMPAr positive modulators. On the basis of crystallographic data of the benzothiadiazines binding mode in the S1S2 GluA2 dimer interface, a set of 5-aryl-2,3-dihydrobenzothiadiazine type compounds has been synthesized and tested. Electrophysiological results suggested that 5-heteroaryl substituents on the benzothiadiazine core like 3-furanyl and 3-thiophenyl dramatically enhance the activity as positive modulators of AMPAr with respect to IDRA21 and cyclothiazide. Mouse brain microdialysis studies have suggested that 7-chloro-5-(3-furyl)-3-methyl-3,4-dihydro-2H-1,2,4-benzothiadiazine 1,1-dioxide crosses the blood鈥揵rain barrier after intraperitoneal injection. Biological results have been rationalized by a computational docking simulation that it has currently employed to design new AMPAr-positive modulator candidates.