Comparative analysis of the neurochemical profile and MAO inhibition properties of N-(furan-2-ylmethyl)-N-methylprop-2-yn-1-amine

Philippe De Deurwaerdère, Claudia Binda, Rémi Corne, Cosima Leone, Aurora Valeri, Massimo Valoti, Rona R. Ramsay, Yagamare Fall, Jose Marco-Contelles

Research output: Contribution to journalArticlepeer-review

Abstract

The regulation of brain monoamine levels is paramount for cognitive functions and the enzymes monoamine oxidases (MAO A and B) play a central role in these processes. The aim of this study was to evaluate whether the pro-cognitive properties exerted by propargylamine N-(furan-2-ylmethyl)-N-methylprop-2-yn-1-amine (F2MPA) were related to changes in monoamine content via MAO inhibition. In vivo microdialysis and ex vivo amine metabolite measurement demonstrated region-specific alterations in monoamine metabolism that differ from both the classic MAO A or MAO B inhibitors clorgyline and L-deprenyl, respectively. Although all the inhibitors (1 and 4 mg/kg) increased cortical serotonin tissue content, only F2MPA increased the levels of cortical noradrenaline. In the striatum, clorgyline (1 mg/kg), but not F2MPA (1 mg/kg), reduced extracellular levels of dopamine metabolites at rest or stimulated by the intrastriatal application of the MAO substrate 3-methoxytyramin. In vitro, F2MPA exhibited a low affinity toward MAO B and MAO A. Nonetheless, it modified the B form of MAO, forming a flavin adduct structurally similar to that with deprenyl. F2MPA was rapidly metabolized in the presence of rat, but not human, microsomes, producing a hydroxylated derivative. In conclusion, the effect of F2MPA on cognition may arise from monoaminergic changes in the cortex, but the role of MAO in this process is likely to be negligible, consistently to the F2MPA poor affinity for MAO.
Original languageEnglish
Article numbercn-2016-00377h
Pages (from-to)1026-1035
Number of pages10
JournalACS Chemical Neuroscience
Volume8
Issue number5
Early online date15 Dec 2016
DOIs
Publication statusPublished - 17 May 2017

Keywords

  • Propargylamines
  • Crystallography
  • Monoamine
  • Neurochemistry
  • Neuroprotection
  • Alzheimer's disease
  • Enzymology

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