Nonselective inhibition of monoamine oxidases A and B by activators of soluble guanylate cyclase.
Several activators of soluble guanylate cyclase were investigated as potential inhibitors of rat liver mitochondrial monoamine oxidases (MAO) A and B. They all fitted into the previously designed "molds" of substrate-inhibitor binding sites of these enzymes. However, only two of them, NO donors (7-nitro-benzotetrazine-1,3-dioxide (7-NBTDO) and benzodifuroxan), caused nonselective inhibition of MAO A and MAO B with IC(50) values of 1.3-1.6 and 6.8-6.3 microM, respectively. The inhibitory effect on both MAO A and MAO B was reduced by mitochondria wash suggesting reversible mode of the enzyme inhibition. There was no correlation between potency of MAO inhibition and activation of human platelet soluble guanylate cyclase. The NO scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide (carboxy-PTIO) had no effect on the manifestation of MAO inhibition by benzodifuroxan and 7-NBTDO; however, at 50 microM concentration carboxy-PTIO caused potent inhibition of MAO A with minor effect on MAO B activity. The data suggest that nonselective inhibition of MAO A and MAO B by benzodifuroxan and 7-NBTDO can be attributed to the properties of the chemical structures of these compounds. The results of the present study demonstrate a real possibility for the development of a new generation of effective reversible nonselective MAO inhibitors exhibiting equal inhibitory activity with respect to both MAO A and MAO B.
Severina
I S
IS
Institute of Biomedical Chemistry, Russian Academy of Medical Sciences, Moscow 119121, Russia.
Axenova
L N
LN
Veselovsky
A V
AV
Pyatakova
N V
NV
Buneeva
O A
OA
Ivanov
A S
AS
Medvedev
A E
AE
D000818:Animals; D001583:Benzoxazoles / Q000737:chemistry / Q000494:pharmacology; D001665:Binding Sites; D006162:Guanylate Cyclase / Q000737:chemistry / Q000378:metabolism*; D006575:Heterocyclic Compounds, 3-Ring / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D008995:Monoamine Oxidase / Q000737:chemistry / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D009574:Nitro Compounds / Q000737:chemistry / Q000494:pharmacology; D010087:Oxides / Q000737:chemistry / Q000494:pharmacology; D011487:Protein Conformation; D051381:Rats; D012995:Solubility; D010069:Oxadiazoles
D001583:Benzoxazoles; D006162:Guanylate Cyclase; D006575:Heterocyclic Compounds, 3-Ring; D008024:Ligands; D008995:Monoamine Oxidase; D008996:Monoamine Oxidase Inhibitors; D009574:Nitro Compounds; D010087:Oxides; C487798:7-nitro-benzotetrazine-1,3-dioxide; C014354:benzofuroxan; D010069:Oxadiazoles