Benextramine derivatives as probes to target human monoamine oxidases

Benextramine is an “old” tetraamine disulfide acting as irreversible alfa-adrenergic antagonist, able to recognize additional targets, such as nicotinic and muscarinic receptors and acetylcholinesterase enzyme, all involved in neurodegeneration. Thanks to its disulfide moiety, benextramine can react with Cys residues of receptors and enzymes leading to a covalent bond resulting in irreversible alteration of the biological activity of the protein target. Benextramine also behaves as competitive M2 muscarinic receptors antagonist and reversible AChE inhibitor. Using benextramine as “template”, various polyamine analogues were designed to improve selectivity and activity towards the multiple targets, besides the cholinergic system, involved in neurodegeneration.(Melchiorre et al, Med Res Rev 2003). Monoamine oxidases (MAO) are well known targets in neurodegenerative diseases ((Bortolato et al., 2008) and both MAO A and MAO B contain Cys residues important for their catalytic activity. On these bases (Hubalek et al., JBC, 2003; Vintem et al., 2005), we thought to evaluate the effect of some benextramine derivatives on MAOs activity, by using a kinetic approach and human recombinant enzymes. Most of the tested compounds were found able to inactivate both MAOs, with a potency and selectivity depending on the type of substituent and on the length of polyamine chain. In particular, increasing the length of the aliphatic chain between the nitrogen atoms of the polyamine scaffold increased the inactivation constant for both the MAOs isoforms. In addition, the catechol moiety on the terminal nitrogen atoms increased the selectivity towards MAO B. In the case of MAO A, an irreversible inactivation was found. Further studies are in progress to elucidate the binding mode of these compounds to MAOs, with the aim to modify their structure in order to improve their affinity and selectivity for potential application in neurodegenerative diseases.