title: Comparative Analysis of the Neurochemical Profile and MAO Inhibition Properties of N-(Furan-2-ylmethyl)-N-methylprop-2-yn-1-amine.
abstract: The regulation of brain monoamine levels is paramount for cognitive functions, and the monoamine oxidase (MAO A and B) enzymes play a central role in these processes. The aim of this study was to evaluate whether the procognitive properties exerted by propargylamine N-(furan-2-ylmethyl)-N-methylprop-2-yn-1-amine (F2MPA) are 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 of the classic MAO A and 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-methoxytyramine. 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, consistent with the poor affinity of F2MPA for MAO.
authors.affiliation: Centre National de la Recherche Scientifique , Institut des Maladies Neurodégénératives, UMR CNRS 5293, 33000 Bordeaux, France.
authors.forename: Philippe
authors.identifier: 0000-0002-1226-3516
authors.initials: P
authors.lastname: De Deurwaerdère
authors.affiliation: Dipartimento di Biologia e Biotecnologie, Università di Pavia , 27100 Pavia, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Binda
authors.affiliation: Centre National de la Recherche Scientifique , Institut des Maladies Neurodégénératives, UMR CNRS 5293, 33000 Bordeaux, France.
authors.forename: Rémi
authors.initials: R
authors.lastname: Corne
authors.affiliation: Dipartimento di Scienze della Vita, Università di Siena , 53100 Siena, Italy.
authors.forename: Cosima
authors.initials: C
authors.lastname: Leone
authors.affiliation: Dipartimento di Chimica, Biologia e Biotecnologie, Università di Perugia , 06123 Perugia, Italy.
authors.forename: Aurora
authors.initials: A
authors.lastname: Valeri
authors.affiliation: Dipartimento di Scienze della Vita, Università di Siena , 53100 Siena, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Valoti
authors.affiliation: Biomedical Sciences Research Complex, University of St Andrews , St Andrews KY16 9ST, U.K.
authors.forename: Rona R
authors.initials: RR
authors.lastname: Ramsay
authors.affiliation: Departamento de Química Orgánica, Universidad de Vigo , 36310 Vigo, Spain.
authors.forename: Yagamare
authors.initials: Y
authors.lastname: Fall
authors.affiliation: Laboratory of Medicinal Chemistry, IQOG, CSIC , 28006 Madrid, Spain.
authors.forename: José
authors.identifier: 0000-0003-0690-0328
authors.initials: J
authors.lastname: Marco-Contelles
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D003010:Clorgyline / Q000494:pharmacology; D005663:Furans / Q000494:pharmacology*; D008297:Male; D017551:Microdialysis; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D009638:Norepinephrine / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012642:Selegiline / Q000494:pharmacology; D012701:Serotonin / Q000378:metabolism*
chemical_list: D005663:Furans; D008996:Monoamine Oxidase Inhibitors; D012642:Selegiline; D012701:Serotonin; D003010:Clorgyline; D009638:Norepinephrine
keywords: Alzheimer’s disease; Propargylamines; crystallography; enzymology; monoamine neurochemistry; neuroprotection