Characteristics of the inhibition of rat brain monoamine oxidase in vitro by MD780515.
The inhibiton of type A and B MAO in rat forebrain crude membrane preparation by MD780515, (3-(4-[(3-cyanophenyl)methoxy]phenyl)-5-(methoxymethyl)-2-oxazolidinone-Centre de Recherche Delalande, France) has been investigated in vitro with 5-hydroxytryptamine and beta-phenylethylamine as substrates. The inhibition of the high-affinity binding of [3H]harmaline, a specific marker of type A MAO, was also studied. In the experimental conditions used, MD780515 appeared to be a pure mixed MAO inhibitor (MAOI) of 5-HT deamination, both Km and Vmax being altered [Ki (Dixon) = Ki, (slope) = 2 nM; Ki (intercept) = 12 nM]. Phenylethylamine oxidation could be considered to be noncompetitively inhibited by MD780515 (Ki (slope) = 78 nM; Ki (intercept) = 103 nM). Dixon and intercept replots were hyperbolic, suggesting that, at high concentrations, PEA could be deaminated by both forms of MAO. This hypothesis was confirmed by biphasic inhibition curves of 80 microM-PEA obtained when MD780515, clorgyline, harmaline and deprenyl were used at MAOIs. MD780515 was a potent inhibitor (IC50 = 1-2 nM) of [3H]harmaline binding. Comparatively, clorgyline, 'cold' harmaline and Lilly 51641 inhibited 3H ligand binding, with IC50 of 5, 7 and 40 nM respectively. In conclusion, MD780515 is a reversible, specific and potent type A MAOI.
D000818:Animals; D001921:Brain / Q000201:enzymology*; D006246:Harmaline / Q000378:metabolism; D066298:In Vitro Techniques; D008297:Male; D008995:Monoamine Oxidase / Q000145:classification; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology; D010080:Oxazoles / Q000494:pharmacology*; D023303:Oxazolidinones; D010627:Phenethylamines / Q000378:metabolism; D051381:Rats; D012701:Serotonin / Q000378:metabolism
D008996:Monoamine Oxidase Inhibitors; D010080:Oxazoles; D023303:Oxazolidinones; D010627:Phenethylamines; C029261:phenethylamine; D012701:Serotonin; D006246:Harmaline; D008995:Monoamine Oxidase; C026234:cimoxatone