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: Bonaiuto Emanuela, Anna Minarini, Vincenzo Tumiatti, Andrea Milelli, Michele Lunelli, Maurizio Pegoraro, Valeria Rizzoli, Maria Luisa Di Paolo
• Journal: Amino acids (Amino Acids) Vol. 42 Issue 2-3 Pg. 913-28 (Feb 2012) ISSN: 1438-2199 [Electronic] Austria
• PMID: 21858471 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Enzyme Inhibitors
• Polyamines
• Amine Oxidase (Copper-Containing)
• Monoamine Oxidase

Topics

• Amine Oxidase (Copper-Containing) (antagonists & inhibitors)
• Circular Dichroism
• Enzyme Inhibitors (pharmacology)
• Kinetics
• Magnetic Resonance Spectroscopy
• Monoamine Oxidase (drug effects)
• Polyamines (pharmacology)
• Spectrometry, Mass, Electrospray Ionization