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

作者：Mattsson Cecilia^*; Svensson Peder; Sonesson Clas

来源：European Journal of Medicinal Chemistry, 2014, 73: 177-186.

DOI：10.1016/j.ejmech.2013.11.035

• Monoamine oxidase A inhibitor
• Dopamine D-2 antagonist
• Coumarin
• DOPAC
• 5-HIAA
• Molecular modeling

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 = 1.46 mu M) or amino (18, IC50 = 3.77 mu 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 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-HIM) but increased 3-methoxytyramine (3-MT) levels.

• 出版日期2014-2-12