Novel targets for “old” polyamine analogues: monoamine oxidases and benextramine derivatives

Benextramine is a well kown tetraamine disulfide acting as irreversible α-adrenergic antagonist and able to hit additional targets involved in neurodegeneration, such as nicotinic and muscarinic receptors and acetylcholinesterase enzyme. The disulfide group of benextramine can react with Cys residues of receptors and enzymes leading to irreversible alterations of their biological activity. On this basis, the potential inhibitory action of ten benextramine analogues was investigated on other well-known targets involved in neurodegenerative diseases, monoamine oxidases (MAOs), whose molecular structures contain various Cys residues. Most of the tested compounds were found able to inactivate both MAO isoforms, with inactivation rate constant values dependent on the polyamine structure as well as on MAO isoforms. Benextramine showed the highest kinact values (0.98 min-1) for MAO A and the “short” CM367 was found the most potent MAO B inactivator (kinact/KIE =1x105 M-1min-1). CM331, with a cathecol moiety at the two terminal ends, showed the best selectivity vs MAO B. Docking experiments highlight the role of Cys323 (in MAO A) and Cys 172 (in MAO B) as targets of the reactive disulfide moiety of benextramine derivatives, suggesting thatthe sterical hindrace of the bound inhibitor may hinder the entrance of substrate towards the FAD cofactor of the active site. The effectiveness of benextramine in inactivating monoamine oxidases in cells was confirmed using human neuroblastoma cell line SH SY5Y. Optimization studies are now in progress with the aim to modify the structure of the described compounds in order to improve their affinity and selectivity for potential application in neurodegenerative diseases.