title: Synthetic polyamines as potential amine oxidase inhibitors: a preliminary study.
abstract: In the last few decades, medicinal chemists have carried out extensive research on synthetic polyamines for use as anticancer drugs and multitarget-directed ligands in neurodegenerative diseases. The aim of this study was to evaluate the effect of some synthetic polyamines as inhibitors of two new potential targets, human semicarbazide-sensitive amine oxidase/vascular adhesion protein-1 (SSAO/VAP-1) and monoamine oxidases B (MAO B), enzymes involved in various multi-factorial diseases such as Alzheimer's disease. N,N'-Dibenzyl-dodecane-1,12-diamine (Bis-Bza-Diado), a newly synthesised compound, and ELP 12, a muscarinic cholinergic M(2) receptor antagonist, were found to behave as reversible and mixed non-competitive inhibitors of both amine oxidases (dissociation constants of about 100 μM). ELP 12 was found to be more selective for SSAO/VAP-1. Combining kinetic and structural approaches, the binding mode of ELP 12 to SSAO/VAP-1 was investigated. ELP 12 may bind at the entrance of the active site channel by ionic interactions with ASP446 and/or ASP180; one end of the polyamine may be accommodated inside the channel, reaching the TPQ cofactor area. The binding of ELP 12 induces rearrangement of the secondary structure of the enzyme and impedes substrate entry and/or product release and catalysis. These structural data reveal that the entrance and the first part of the SSAO/VAP-1 channel may be considered as a new target area, or a "secondary binding site", for modulators of human SSAO/VAP-1 activity. These results indicate ELP 12 and Bis-Bza-Diado as new "skeletons" for the development of novel SSAO/VAP-1 and MAO B inhibitors.
authors.affiliation: Department of Biological Chemistry, University of Padova, Via G. Colombo 3, 35131, Padua, Italy.
authors.forename: Bonaiuto
authors.initials: B
authors.lastname: Emanuela
authors.forename: Anna
authors.initials: A
authors.lastname: Minarini
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Tumiatti
authors.forename: Andrea
authors.initials: A
authors.lastname: Milelli
authors.forename: Michele
authors.initials: M
authors.lastname: Lunelli
authors.forename: Maurizio
authors.initials: M
authors.lastname: Pegoraro
authors.forename: Valeria
authors.initials: V
authors.lastname: Rizzoli
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Di Paolo
mesh_terms: D006631:Amine Oxidase (Copper-Containing) / Q000037:antagonists & inhibitors*; D002942:Circular Dichroism; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D008995:Monoamine Oxidase / Q000187:drug effects*; D011073:Polyamines / Q000494:pharmacology*; D021241:Spectrometry, Mass, Electrospray Ionization
chemical_list: D004791:Enzyme Inhibitors; D011073:Polyamines; D006631:Amine Oxidase (Copper-Containing); D008995:Monoamine Oxidase