title: A novel series of 6-substituted 3-(pyrrolidin-1-ylmethyl)chromen-2-ones as selective monoamine oxidase (MAO) A inhibitors.
abstract: 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 μM) or amino (18, IC50 = 3.77 μM) 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-HIAA) but increased 3-methoxytyramine (3-MT) levels.
authors.affiliation: Medicinal Chemistry, NeuroSearch Sweden AB, Biotech Center, Arvid Wallgrens Backe 20, SE-413 46 Gothenburg, Sweden. Electronic address: cecilia.m.mattsson@gmail.com.
authors.forename: Cecilia
authors.initials: C
authors.lastname: Mattsson
authors.affiliation: Medicinal Chemistry, NeuroSearch Sweden AB, Biotech Center, Arvid Wallgrens Backe 20, SE-413 46 Gothenburg, Sweden. Electronic address: peder.svensson@astrazeneca.com.
authors.forename: Peder
authors.initials: P
authors.lastname: Svensson
authors.affiliation: Medicinal Chemistry, NeuroSearch Sweden AB, Biotech Center, Arvid Wallgrens Backe 20, SE-413 46 Gothenburg, Sweden. Electronic address: clas.sonesson@irlab.se.
authors.forename: Clas
authors.initials: C
authors.lastname: Sonesson
mesh_terms: D000818:Animals; D001665:Binding Sites; D002867:Chromones / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D017551:Microdialysis; D008958:Models, Molecular; D015394:Molecular Structure; D008995:Monoamine Oxidase / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D018377:Neurotransmitter Agents / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D012995:Solubility; D013329:Structure-Activity Relationship
chemical_list: D002867:Chromones; D008996:Monoamine Oxidase Inhibitors; D018377:Neurotransmitter Agents; D008995:Monoamine Oxidase
keywords: 5-HIAA; Coumarin; DOPAC; Dopamine D(2) antagonist; Molecular modeling; Monoamine oxidase A inhibitor