title: FA-70, a novel selective and irreversible monoamine oxidase-A inhibitor: effect on monoamine metabolism in mouse cerebral cortex.
abstract: A series of indolealkylamine derivatives has been previously designed and evaluated with the aim of finding the most potent and selective novel monoamine oxidase (MAO) inhibitors to be used in the therapy of neurological and affective disorders. Among them, FA70, a 5-hydroxy-indolealkylamine derivative, has been characterized in vitro as a potent, irreversible, and mechanism-based inhibitor of the MAO-A isoform. The comparison with clorgyline, analyzed under the same experimental conditions, confirmed FA70 as the most potent MAO-A inhibitor. The ex vivo effect of FA70 on MAO activity in mouse cerebral cortex was similar to that observed in vitro, showing more efficacy than in peripheral tissues. The ex vivo effect of FA70 on amine metabolism also was evaluated after acute and chronic treatment, and the results showed that between both MAO isoforms, MAO-A is the only one responsible for monoamine metabolism in this region of the brain. The ex vivo effect of FA70 on dopamine content was correlated with the activation effect on tyrosine hydroxylase activity, the enzyme responsible for the regulation of the limiting step in catecholamine synthesis.
authors.affiliation: Departament Bioquimica i Biologia Molecular, Facultat de Medicina, Universitat Autónoma de Barcelona, Campus Universitari de Bellaterra, Barcelona, Spain.
authors.forename: J A
authors.initials: JA
authors.lastname: Morón
authors.forename: V
authors.initials: V
authors.lastname: Pérez
authors.forename: M
authors.initials: M
authors.lastname: Pastó
authors.forename: J M
authors.initials: JM
authors.lastname: Lizcano
authors.forename: M
authors.initials: M
authors.lastname: Unzeta
mesh_terms: D000818:Animals; D015306:Biogenic Monoamines / Q000378:metabolism*; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism*; D003010:Clorgyline / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D066298:In Vitro Techniques; D007211:Indoles / Q000494:pharmacology*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008995:Monoamine Oxidase / Q000145:classification / Q000502:physiology*; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D020033:Protein Isoforms / Q000037:antagonists & inhibitors; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D015306:Biogenic Monoamines; C404150:FA 70; D007211:Indoles; D008996:Monoamine Oxidase Inhibitors; D020033:Protein Isoforms; D014446:Tyrosine 3-Monooxygenase; D008995:Monoamine Oxidase; D003010:Clorgyline; D004298:Dopamine