Synthesis, resolution, stereochemistry, and molecular modeling of (R)- and (S)-2-acetyl-1-(4′-chlorophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline AMPAR antagonists

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• 作者：Rosaria Gitto ; Rita Ficarra ; Rosanna Stancanelli ; Marta Guardo ; Laura De Luca ; Maria Letizia Barreca ; Benedetta Pagano ; Archimede Rotondo ; Giuseppe Bruno ; Emilio Russo ; et al.
• 关键词：Tetrahydroisoquinoline ; Microwave-assisted synthesis ; Anticonvulsant ; AMPA-antagonist ; Molecular modeling ; Enantiomeric resolution ; X-ray crystal structure
• 刊名：Bioorganic and Medicinal Chemistry
• 出版年：2007
• 出版时间：15 August 2007
• 年：2007
• 卷：15
• 期：16
• 页码：5417-5423
• 全文大小：269 K

文摘

Recently we identified (R,S)-2-acetyl-1-(4′-chlorophenyl)-6,7-dimethoxy-1,2,3,4-tetrahydroisoquinoline (6) as a potent non-competitive AMPA receptor antagonist able to prevent epileptic seizures. We report here the optimized synthesis of compound 6, its resolution by chiral preparative HPLC, and the absolute configuration of (R)-enantiomer established by X-ray diffractometry. The biological tests of the single enantiomers revealed that higher anticonvulsant and antagonistic effects reside in (R)-enantiomer as also suggested by molecular modeling studies.