Introduction: The efficacy of L-dopa in the treatment of Parkinson’s disease depends on its
metabolic conversion to dopamine in the brain, however extensive peripheral metabolism of L-dopa
diminishes its availability for uptake into the brain. L-Dopa is extensively decarboxylated in the gastrointestinal
tract and peripheral tissues by Aromatic L-Amino Acid Decarboxylase (AADC), and
AADC inhibitors are thus frequently combined with L-dopa therapy. When AADC is inhibited, 3-Omethylation
Catalysed by Catechol-O-Methyltransferase (COMT) becomes a dominant metabolic
pathway for L-dopa, and COMT inhibitors may thus also be used as adjuncts to L-dopa in Parkinson’s
disease. Monoamine Oxidase (MAO), in turn, metabolises dopamine in the brain, and MAO-B inhibitors
may exert a dopamine sparing effect in the brain.
Materials & Methods: Based on the roles of COMT and MAO in the metabolism of L-dopa and dopamine,
the present study attempts to discover novel dual inhibitors of these enzymes. For this purpose,
nitrocatechol derivatives of chalcone were synthesised and evaluated as inhibitors of COMT and
MAO. The chalcone class of compounds is well known to potently inhibit MAO-B, while nitrocatechol
derivatives (e.g. tolcapone and entacapone) are clinically used COMT inhibitors.
Results: The results document that all of the derivatives are high potency in vitro inhibitors of rat liver
COMT with IC50 values ranging from 0.07 to 0.29 μM. Under these experimental conditions, tolcapone
and entacapone display IC50 values of 0.26 µM and 0.25 µM, respectively. The chalcones are
less potent as inhibitors of MAO with the most potent inhibitor possessing a Ki of 4.6 µM for the in
vitro inhibition of human MAO-B.
Conclusion: This study shows that nitrocatechol derivatives of chalcone may act as COMT and
MAO-B inhibitors, and proposes a general strategy for further enhancing MAO-B inhibition while retaining
the potent COMT inhibition activity of this class.