Antagonism between long acting Monoamine Oxidase Inhibitors (MAOI) and MD780515, a new specific and reversible MAOI

The inhibition of type A and B monoamine oxidase (MAO A and B) in rat brain, liver and heart by MD780515, 3-4-(3 cyanophenylmethoxy) phenyl]-5-(methoxymethyl)-2-oxazolidinone, has been investigated ex vivo with 5-hydroxytryptamine (5-HT) and β-phenylethylamine (PEA) as substrates. MAO A was strongly inhibited for four hours after oral administration of 10 mg/kg MD780515 (maximum inhibition : 72%, 86% and 83% in brain, liver and heart respectively. In contrast, in heart where PEA is deaminated by type A MAO, the predominant form of MAO in that tissue, the inhibition was 68% 30 minutes after administration of the compound. In all cases, MAO activities reached control values 24 hours after drug administration (10 mg/kg), whereas some inhibitory activity was still present 24 hours after oral administration of higher doses. The strong MAO A inhibition (68 to 83%) remaining in the three tissues 24 hours after oral administration of clorgyline (5 mg/kg) was completely removed by pretreatment with MD780515 (10 mg/kg). In the same conditions, MD780515 protected against the inhibition (53%) by clorgyline of PEA deamination in heart. Oral pretreatment with increasing doses of MD780515 (2.6 to 84 mg/kg) gradually removed brain MAO A inhibition caused by clorgyline (92%, 28.2 mg/kg) or tranylcypromine (88%, 4.8 mg/kg), the complete removal being observed at the dose of 21 mg/kg of MD780515 for clorgyline, and at 42 mg/kg for tranylcypromine. Inhibition of brain MAO B by tranylcypromine (96%) was not modified by pretreatment with the same range of oral doses of MD780515. The results are consistent with a specific and reversible inhibition of MAO A activity by MD780515 which can protect against long acting MAO A inhibitory effects of clorgyline and tranylcypromine. MD780515 enhances the selectivity of tranylcypromine.