title: cis-Cyclopropylamines as mechanism-based inhibitors of monoamine oxidases.
abstract: Cyclopropylamines, inhibitors of monoamine oxidases (MAO) and lysine-specific demethylase (LSD1), provide a useful structural scaffold for the design of mechanism-based inhibitors for treatment of depression and cancer. For new compounds with the less common cis relationship and with an alkoxy substituent at the 2-position of the cyclopropyl ring, the apparent affinity determined from docking experiments revealed little difference between the enantiomers. Using the racemate, kinetic parameters for the reversible and irreversible inhibition of MAO were determined. No inhibition of LSD1 was observed. For reversible inhibition, most compounds gave high IC50 values with MAO A, but sub-micromolar values with MAO B. After pre-incubation of the cyclopropylamine with the enzyme, the inhibition was irreversible for both MAO A and MAO B, and the activity was not restored by dilution. Spectral changes during inactivation of MAO A included bleaching at 456 nm and an increased absorbance at 400 nm, consistent with flavin modification. These derivatives are MAO B-selective irreversible inhibitors that do not show inhibition of LSD1. The best inhibitor was cis-N-benzyl-2-methoxycyclopropylamine, with an IC50 of 5 nm for MAO B and 170 nm for MAO A after 30 min pre-incubation. This cis-cyclopropylamine is over 20-fold more effective than tranylcypromine, so may be studied as a lead for selective inhibitors of MAO B that do not inhibit LSD1.
authors.affiliation: Biomedical Sciences Research Complex, University of St Andrews, UK.
authors.forename: Thomas
authors.initials: T
authors.lastname: Malcomson
authors.affiliation: Department of Bioinformatics and Genetics, Kadir Has University, Istanbul, Turkey.
authors.forename: Kemal
authors.initials: K
authors.lastname: Yelekci
authors.affiliation: School of Pharmacy, University of East Anglia, Norwich, UK.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Borrello
authors.affiliation: School of Pharmacy, University of East Anglia, Norwich, UK.
authors.forename: A
authors.initials: A
authors.lastname: Ganesan
authors.affiliation: Department of Sustainable Organic Chemistry and Technology, Ghent University, Belgium.
authors.forename: Elena
authors.initials: E
authors.lastname: Semina
authors.affiliation: Department of Sustainable Organic Chemistry and Technology, Ghent University, Belgium.
authors.forename: Norbert
authors.initials: N
authors.lastname: De Kimpe
authors.affiliation: Department of Sustainable Organic Chemistry and Technology, Ghent University, Belgium.
authors.forename: Sven
authors.initials: S
authors.lastname: Mangelinckx
authors.affiliation: Biomedical Sciences Research Complex, University of St Andrews, UK.
authors.forename: Rona R
authors.initials: RR
authors.lastname: Ramsay
mesh_terms: D000928:Antidepressive Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D020134:Catalytic Domain; D003521:Cyclopropanes / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D056466:Histone Demethylases / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D066298:In Vitro Techniques; D007700:Kinetics; D008958:Models, Molecular; D008995:Monoamine Oxidase / Q000737:chemistry / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D014191:Tranylcypromine / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology
chemical_list: D000928:Antidepressive Agents; D003521:Cyclopropanes; D008996:Monoamine Oxidase Inhibitors; D014191:Tranylcypromine; C067351:cyclopropylamine; D056466:Histone Demethylases; D008995:Monoamine Oxidase; C495195:KDM1A protein, human
keywords: cyclopropylamine; docking; flavin adduct; mechanism-based inhibitor; monoamine oxidase