title: The inhibition of monoamine oxidase by phenformin and pentamidine.
abstract: A computational study has suggested that phenformin, an oral hypoglycaemic drug, may bind to the active sites of the monoamine oxidase (MAO) A and B enzymes. The present study therefore investigates the MAO inhibitory properties of phenformin. Pentamidine, a structurally related diamidine compound, has previously been reported to be a MAO inhibitor and was included in this study as a reference compound. Using recombinant human MAO-A and MAO-B, this study finds that phenformin acts as a moderately potent MAO-A selective inhibitor with an IC50 value of 41 µM. Pentamidine, on the other hand, potently inhibits both MAO-A and MAO-B with IC50 values of 0.61 μM and 0.22 μM, respectively. An examination of the recoveries of the enzymatic activities after dilution and dialysis of the enzyme-inhibitor complexes shows that both compounds interact reversibly with the MAO enzymes. A kinetic analysis suggests that pentamidine acts as a competitive inhibitor with estimated Ki values of 0.41 μM and 0.22 μM for the inhibition of MAO-A and MAO-B, respectively. Phenformin also exhibited a competitive mode of MAO-A inhibition with an estimated Ki value of 65 µM. This study concludes that biguanide and amidine functional groups are most likely important structural features for the inhibition of the MAOs by phenformin and pentamidine, and compounds containing these and closely related functional groups should be considered as potential MAO inhibitors. Furthermore, the biguanide and amidine functional groups may act as useful moieties in the future design of MAO inhibitors.
authors.affiliation: Pharmaceutical Chemistry, School of Pharmacy, North-West University, Potchefstroom, South Africa.
authors.forename: M
authors.initials: M
authors.lastname: Barkhuizen
authors.affiliation: Centre of Excellence for Pharmaceutical Sciences, School of Pharmacy, North-West University, Potchefstroom, South Africa.
authors.forename: A
authors.initials: A
authors.lastname: Petzer
authors.affiliation: Pharmaceutical Chemistry, School of Pharmacy, North-West University, Potchefstroom, South Africa.
authors.forename: J P
authors.initials: JP
authors.lastname: Petzer
mesh_terms: D006801:Humans; D007004:Hypoglycemic Agents / Q000008:administration & dosage / Q000494:pharmacology; D020128:Inhibitory Concentration 50; D008995:Monoamine Oxidase / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D010419:Pentamidine / Q000008:administration & dosage / Q000494:pharmacology*; D010629:Phenformin / Q000008:administration & dosage / Q000494:pharmacology*; D011994:Recombinant Proteins
chemical_list: D007004:Hypoglycemic Agents; D008996:Monoamine Oxidase Inhibitors; D011994:Recombinant Proteins; D010419:Pentamidine; D010629:Phenformin; D008995:Monoamine Oxidase