Monoamine oxidases, (MAOs) have been widely recognised as important pharmacological targets for the treatment of mood disorders (anxiety, depression) and neurodegeneration (Parkinson's disease, PD) as the results of their effects on monoamine metabolism and level. The products deriving from hMAO enzymatic activity are aldehydes and the ammonium ion, while the by-product hydrogen peroxide is formed in order to regenerate the catalytically active form of the FAD cofactor. Although aldehydes do not appear to accumulate in the healthy brain, some studies have shown that elevated concentration of these products may exert cytotoxic effects. MAO-mediated oxidative stress has been associated with different neurodegenerative pathologies as well as cardiomyopathies. This suggests that reducing the activity of the hMAOs could be useful in order to protect cell. Aims of this project are: a) to design new irreversible and reversible MAO inhibitors as therapeutic tools for neurodegenerative phatologies b) to perform a virtual screening for identifying new inhibitors.
For several years our group has been working on hMAOs inhibitors as potential co-adjuvants for the treatment of neurodegenerative diseases.
Inhibitors of MAO-A and MAO-B have thus been used for the treatment of diseases that result from deficient neurotransmitter levels. MAO-A inhibitors increase central serotonin levels and are used for the treatment of major depression. MAO-B inhibitors are used in the treatment of Parkinson¿s disease where they reduce the MAO-catalysed breakdown of dopamine. This is expected to enhance striatal dopaminergic activity leading to the improvement of motor symptoms. MAO-B inhibitors are often combined with l-Dopa, the metabolic precursor of dopamine, in Parkinson¿s disease therapy. Selective MAO-B inhibitors may also possess disease modifying properties by protecting against neurodegeneration in Parkinson¿s disease. The neuroprotective effect of MAO-B inhibitors may, at least in part, be attributed to the reduction of the central formation of toxic metabolic by-products (hydrogen peroxide and aldehydes) of the MAO catalytic cycle.
The series of benzothiophen-3-ol derivatives was demonstrated to be a very interesting scaffold to design high potency hMAOs inhibitors, with IC50 values in the low micromolar to nanomolar range. Moreover, the introduction of specific substituents on the phenyl resulted in highly selective inhibition of this isozyme. These compounds were also characterised by an effective ex vivo hMAO-B inhibition as well as by limited antioxidant and chelating properties.
We will combine our knowledge and strengths, designing focused chemical libraries, suitable to targets not yet having proper drug.