title: Kinetic and structural analysis of the irreversible inhibition of human monoamine oxidases by ASS234, a multi-target compound designed for use in Alzheimer's disease.
abstract: Monoamine oxidases (MAO) and cholinesterases are validated targets in the design of drugs for the treatment of Alzheimer's disease. The multi-target compound N-((5-(3-(1-benzylpiperidin-4-yl)propoxy)-1-methyl-1H-indol-2-yl)methyl)-N-methylprop-2-yn-1-amine (ASS234), bearing the MAO-inhibiting propargyl group attached to a donepezil moiety that inhibits cholinesterases, retained activity against human acetyl- and butyryl-cholinesterases. The inhibition of MAO A and MAO B by ASS234 was characterized and compared to other known MAO inhibitors. ASS234 was almost as effective as clorgyline (kinact/KI=3×10(6) min(-1)M(-1)) and was shown by structural studies to form the same N5 covalent adduct with the FAD cofactor.
authors.affiliation: Departamento de Bioquímica i Biología Molecular, Institute of Neuroscience, Facultat de Medicina, Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain.
authors.forename: Gerard
authors.initials: G
authors.lastname: Esteban
authors.affiliation: Biomedical Sciences Research Complex, University of St Andrews, North Haugh, St Andrews KY16 8QP, UK.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Allan
authors.affiliation: Laboratorio de Química Medica (IQOG, CSIC), C/Juan de la Cierva 3, 28006 Madrid, Spain.
authors.forename: Abdelouahid
authors.initials: A
authors.lastname: Samadi
authors.affiliation: Department of Biology and Biotechnology, University of Pavia, Pavia 27100, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Mattevi
authors.affiliation: Departamento de Bioquímica i Biología Molecular, Institute of Neuroscience, Facultat de Medicina, Universitat Autònoma de Barcelona, 08193 Bellaterra, Barcelona, Spain.
authors.forename: Mercedes
authors.initials: M
authors.lastname: Unzeta
authors.affiliation: Laboratorio de Química Medica (IQOG, CSIC), C/Juan de la Cierva 3, 28006 Madrid, Spain.
authors.forename: José
authors.initials: J
authors.lastname: Marco-Contelles
authors.affiliation: Department of Biology and Biotechnology, University of Pavia, Pavia 27100, Italy. Electronic address: claudia.binda@unipv.it.
authors.forename: Claudia
authors.initials: C
authors.lastname: Binda
authors.affiliation: Biomedical Sciences Research Complex, University of St Andrews, North Haugh, St Andrews KY16 8QP, UK. Electronic address: rrr@st-and.ac.uk.
authors.forename: Rona R
authors.initials: RR
authors.lastname: Ramsay
mesh_terms: D000110:Acetylcholinesterase / Q000737:chemistry; D002091:Butyrylcholinesterase / Q000737:chemistry; D003010:Clorgyline / Q000737:chemistry; D000077265:Donepezil; D005182:Flavin-Adenine Dinucleotide / Q000737:chemistry; D006801:Humans; D007189:Indans / Q000737:chemistry; D007211:Indoles / Q000737:chemistry*; D007700:Kinetics; D008958:Models, Molecular; D008995:Monoamine Oxidase / Q000737:chemistry* / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000737:chemistry*; D018696:Neuroprotective Agents / Q000737:chemistry*; D010880:Piperidines / Q000737:chemistry*; D011994:Recombinant Proteins / Q000737:chemistry / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000235:genetics / Q000378:metabolism
chemical_list: D007189:Indans; D007211:Indoles; D008996:Monoamine Oxidase Inhibitors; C570530:N-((5-(3-(1-benzylpiperidin-4-yl)propoxy)-1-methyl-1H-indol-2-yl)methyl)-N-methylprop-2-yn-1-amine; D018696:Neuroprotective Agents; D010880:Piperidines; D011994:Recombinant Proteins; D005182:Flavin-Adenine Dinucleotide; D000077265:Donepezil; D008995:Monoamine Oxidase; D000110:Acetylcholinesterase; D002091:Butyrylcholinesterase; D003010:Clorgyline
keywords: ASS234; Alzheimer’s disease; Crystal structure; Flavin adduct; Multi-target drug; PF9601N