Synthetic polyamines as potential amine oxidases inhibitors: a preliminary study.

Natural polyamines, such as putrescine and spermine, are widely distributed in living organism and they are involved in the regulation of many cellular functions (from cell growth, to apoptosis and cell death). The binding of polyamines to a variety of receptors has been widely reported. It has been found that appropriate modifications of the chain length separating the nitrogen atoms of polyamines and the insertion of substituents are able to modulate both their affinity and selectivity for a receptor/protein (1). On these bases, synthetic polyamines have been proposed as a “universal template” to develop multi-target ligands in the treatment of multifunctional diseases, such as neurodegenerative diseases (2). Here we report about our preliminary results obtained using some synthetic polyamines as potential inhibitors of Semicarbazide-sensitive amine oxidase/Vascular Adhesion Protein-1 (SSAO/VAP-1) and of monoamine oxidase type A (MAO A), enzymes involved in neurodegenerative diseases, such as Alzheimer’s and Parkinson’s diseases (3-6). We tested six methoctramine–related polyamines using human adipocyte lysates as source of SSAO/VAP-1 and of MAO A. From the kinetic studies carried out so far, we found that most of the tested compounds behave as mixed non-competitive and reversible inhibitors, with inhibition constants ranging from 90 to 600 microM. In particular, the preliminary results suggest that ELP-12, a muscarinic M2 receptor antagonist (7), might be considered a good “skeleton” to develop new potential inhibitors for SSAO/VAP-1. Additionally, we also found that the introduction of reactive groups on polyamine backbone, as in the novel compound NT-27, led to irreversible inhibitor for MAO A, with an inhibition constant of about 20 microM after 10 minutes of incubation time. Further studies are in progress to understand the binding modes of these compounds to SSAO/VAP-1 and MAO A and, in such a way, to modify their structure to improve their affinity and selectivity.