title: The monoamine oxidase inhibition properties of selected structural analogues of methylene blue.
abstract: The thionine dye, methylene blue (MB), is a potent inhibitor of monoamine oxidase (MAO) A, a property that may, at least in part, mediate its antidepressant effects in humans and animals. The central inhibition of MAO-A by MB has also been linked to serotonin toxicity (ST) which may arise when MB is used in combination with serotonergic drugs. Structural analogues and the principal metabolite of MB, azure B, have also been reported to inhibit the MAO enzymes, with all compounds exhibiting specificity for the MAO-A isoform. To expand on the structure-activity relationships (SARs) of MAO inhibition by MB analogues, the present study investigates the human MAO inhibition properties of five MB analogues: neutral red, Nile blue, new methylene blue, cresyl violet and 1,9-dimethyl methylene blue. Similar to MB, these analogues also are specific MAO-A inhibitors with cresyl violet (IC50=0.0037μM), Nile blue (IC50=0.0077μM) and 1,9-dimethyl methylene blue (IC50=0.018μM) exhibiting higher potency inhibition compared to MB (IC50=0.07μM). Nile blue also represents a potent MAO-B inhibitor with an IC50value of 0.012μM. From the results it may be concluded that non-thionine MB analogues (e.g. cresyl violet and Nile blue) also may exhibit potent MAO inhibition, a property which should be considered when using these compounds in pharmacological studies. Benzophenoxazines such as cresyl violet and Nile blue are, similar to phenothiazines (e.g. MB), representative of high potency MAO-A inhibitors with a potential risk of ST.
authors.affiliation: Pharmaceutical Chemistry, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa; Centre of Excellence for Pharmaceutical Sciences, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa.
authors.forename: Anzelle
authors.initials: A
authors.lastname: Delport
authors.affiliation: Centre of Excellence for Pharmaceutical Sciences, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa; Pharmacology, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa.
authors.forename: Brian H
authors.initials: BH
authors.lastname: Harvey
authors.affiliation: Pharmaceutical Chemistry, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa; Centre of Excellence for Pharmaceutical Sciences, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa.
authors.forename: Anél
authors.initials: A
authors.lastname: Petzer
authors.affiliation: Pharmaceutical Chemistry, School of Pharmacy, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa; Centre of Excellence for Pharmaceutical Sciences, North-West University, Private Bag X6001, Potchefstroom 2520, South Africa. Electronic address: jacques.petzer@nwu.ac.za.
authors.forename: Jacobus P
authors.initials: JP
authors.lastname: Petzer
mesh_terms: D048588:Benzoxazines / Q000494:pharmacology; D001665:Binding Sites; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008751:Methylene Blue / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D062105:Molecular Docking Simulation; D015394:Molecular Structure; D008995:Monoamine Oxidase / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D009499:Neutral Red / Q000494:pharmacology; D010078:Oxazines / Q000494:pharmacology; D011485:Protein Binding; D011994:Recombinant Proteins / Q000378:metabolism; D018570:Risk Assessment; D020230:Serotonin Syndrome / Q000139:chemically induced / Q000201:enzymology; D013329:Structure-Activity Relationship
chemical_list: D048588:Benzoxazines; D008996:Monoamine Oxidase Inhibitors; D010078:Oxazines; D011994:Recombinant Proteins; C035184:new methylene blue; C008619:Nile Blue; D009499:Neutral Red; C028911:cresyl violet; D008995:Monoamine Oxidase; C579458:monoamine oxidase A, human; D008751:Methylene Blue; C016401:1,9-dimethylmethylene blue
keywords: Cresyl violet; Inhibition; MAO; Methylene blue; Monoamine oxidase; Nile blue