A novel series of 6-substituted 3-(pyrrolidin-1-ylmethyl)chromen-2-ones as selective monoamine oxidase (MAO) A inhibitors

详细信息    查看全文

• 作者：Cecilia Mattsson ; Peder Svensson ; Clas Sonesson
• 关键词：Monoamine oxidase A inhibitor ; Dopamine D2 antagonist ; Coumarin ; DOPAC ; 5-HIAA ; Molecular modeling
• 刊名：European Journal of Medicinal Chemistry
• 出版年：12 February, 2014
• 年：2014
• 卷：73
• 期：Complete
• 页码：177-186
• 全文大小：864 K

文摘

A series of 6-substituted 3-(pyrrolidin-1-ylmethyl)chromen-2-ones (coumarins) have been synthesized and their inhibitory activity to human monoamine oxidase A (MAO A) and B (MAO B) determined. Incorporation of a basic amino function in the C3 position together with substitution at the C6 position produced novel coumarin compounds with selectivity for the MAO A subtype. Substitution in the C6 position with small hydrophilic groups such as hydroxy (19, IC₅₀聽=聽1.46聽渭M) or amino (18, IC₅₀聽=聽3.77聽渭M) gave the most potent and selective compounds for MAO A. These compounds also showed excellent aqueous solubility properties. Compound 18 [6-amino-3-(pyrrolidin-1-ylmethyl)chromen-2-one] administrated in聽vivo induced in rat brain a neurotransmitter metabolite profile typical of MAO A inhibition: decreased 3,4-dihydroxyphenylacetic acid (DOPAC) and 5-hydroxyindoleacetic acid (5-HIAA) but increased 3-methoxytyramine (3-MT) levels.