Background:
The most effective symptomatic treatment of Parkinson’s disease remains
the metabolic precursor of dopamine, L-dopa. To enhance the efficacy of L-dopa, it is often combined
with inhibitors of the enzymes, catechol-O-methyltransferase (COMT) and monoamine oxidase
(MAO) B, key metabolic enzymes of L-dopa and dopamine.
Objective:
This study attempted to discover compounds that exhibit dual inhibition of COMT and
MAO-B among a library of 40 structurally diverse natural compounds. Such dual acting inhibitors
may be effective as adjuncts to L-dopa and offer enhanced value in the management of Parkinson’s
disease.
Methods:
Selected natural compounds were evaluated as in vitro inhibitors of rat liver COMT and
recombinant human MAO. Reversibility of MAO inhibition was investigated by dialysis.
Results:
Among the natural compounds morin (IC50 = 1.32 µM), chlorogenic acid (IC50 = 6.17 µM),
(+)-catechin (IC50 = 0.86 µM), alizarin (IC50 = 0.88 µM), fisetin (IC50 = 5.78 µM) and rutin (IC50 =
25.3 µM) exhibited COMT inhibition. Among these active COMT inhibitors only morin (IC50 = 16.2
µM), alizarin (IC50 = 8.16 µM) and fisetin (IC50 = 7.33 µM) were noteworthy MAO inhibitors, with
specificity for MAO-A.
Conclusion:
None of the natural products investigated here are dual COMT/MAO-B inhibitors.
However, good potency COMT inhibitors have been identified, which may serve as leads for future
development of COMT inhibitors.