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cis-Cyclopropylamines as mechanism-based inhibitors of monoamine oxidases

(2015) FEBS JOURNAL. 282(16). p.3190-3198
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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 MAOA and MAOB, and the activity was not restored by dilution. Spectral changes during inactivation of MAOA included bleaching at 456nm and an increased absorbance at 400nm, consistent with flavin modification. These derivatives are MAOB-selective irreversible inhibitors that do not show inhibition of LSD1. The best inhibitor was cis-N-benzyl-2-methoxycyclopropylamine, with an IC50 of 5nm for MAOB and 170nm for MAOA after 30min pre-incubation. This cis-cyclopropylamine is over 20-fold more effective than tranylcypromine, so may be studied as a lead for selective inhibitors of MAOB that do not inhibit LSD1.
Keywords
cyclopropylamine, mechanism-based inhibitor, docking, flavin adduct, monoamine oxidase, HISTONE DEMETHYLASE LSD1, IRREVERSIBLE INHIBITORS, MULTIPLE FORMS, AMINE OXIDASES, BINDING-SITE, TRANYLCYPROMINE, DERIVATIVES, TRANS-2-PHENYLCYCLOPROPYLAMINE, INACTIVATION, EFFICACY

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Chicago
Malcomson, Thomas, Kemal Yelekci, Maria Teresa Borrello, A Ganesan, Elena Semina, Norbert De Kimpe, Sven Mangelinckx, and Rona R Ramsay. 2015. “cis-Cyclopropylamines as Mechanism-based Inhibitors of Monoamine Oxidases.” Febs Journal 282 (16): 3190–3198.
APA
Malcomson, T., Yelekci, K., Borrello, M. T., Ganesan, A., Semina, E., De Kimpe, N., Mangelinckx, S., et al. (2015). cis-Cyclopropylamines as mechanism-based inhibitors of monoamine oxidases. FEBS JOURNAL, 282(16), 3190–3198.
Vancouver
1.
Malcomson T, Yelekci K, Borrello MT, Ganesan A, Semina E, De Kimpe N, et al. cis-Cyclopropylamines as mechanism-based inhibitors of monoamine oxidases. FEBS JOURNAL. 2015;282(16):3190–8.
MLA
Malcomson, Thomas, Kemal Yelekci, Maria Teresa Borrello, et al. “cis-Cyclopropylamines as Mechanism-based Inhibitors of Monoamine Oxidases.” FEBS JOURNAL 282.16 (2015): 3190–3198. Print.
@article{7017305,
  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 MAOA and MAOB, and the activity was not restored by dilution. Spectral changes during inactivation of MAOA included bleaching at 456nm and an increased absorbance at 400nm, consistent with flavin modification. These derivatives are MAOB-selective irreversible inhibitors that do not show inhibition of LSD1. The best inhibitor was cis-N-benzyl-2-methoxycyclopropylamine, with an IC50 of 5nm for MAOB and 170nm for MAOA after 30min pre-incubation. This cis-cyclopropylamine is over 20-fold more effective than tranylcypromine, so may be studied as a lead for selective inhibitors of MAOB that do not inhibit LSD1.},
  author       = {Malcomson, Thomas and Yelekci, Kemal and Borrello, Maria Teresa and Ganesan, A and Semina, Elena and De Kimpe, Norbert and Mangelinckx, Sven and Ramsay, Rona R},
  issn         = {1742-464X},
  journal      = {FEBS JOURNAL},
  keyword      = {cyclopropylamine,mechanism-based inhibitor,docking,flavin adduct,monoamine oxidase,HISTONE DEMETHYLASE LSD1,IRREVERSIBLE INHIBITORS,MULTIPLE FORMS,AMINE OXIDASES,BINDING-SITE,TRANYLCYPROMINE,DERIVATIVES,TRANS-2-PHENYLCYCLOPROPYLAMINE,INACTIVATION,EFFICACY},
  language     = {eng},
  number       = {16},
  pages        = {3190--3198},
  title        = {cis-Cyclopropylamines as mechanism-based inhibitors of monoamine oxidases},
  url          = {http://dx.doi.org/10.1111/febs.13260},
  volume       = {282},
  year         = {2015},
}

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