Characteristics of the Inhibition of Rat Brain Monoamine Oxidase In Vitro by MD780515

Abstract: The inhibition 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 β-phenylethyl-amine 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 K_m , and V_max being altered [K₁ (Dixon) = K_i , (slope) = 2 nM; K_i (intercept) = 12 nM]. Phenylethylamine oxidation could be considered to be noncompetitively inhibited by MD780515 (K_i (slope) = 78 nM; K_i , (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 μM-PEA obtained when MD7805 15 , clorgyline, harmaline and deprenyl were used as 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.