Biochemical and pharmacologic properties of 2614W94, a reversible, competitive inhibitor of monoamine oxidase-A

2614W94 [3-(1-trifluoromethyl)ethoxyphenoxathiin 10,10-dioxide] is a select ive, reversible inhibitor of monoamine oxidase-A with a competitive mechani sm of inhibition and a K-i value of 1.6 nM with serotonin as substrate. In pretreated rats, the ED50 value after single oral dosing was 1.7 mg/kg, sim ilar to an ED50 value of 1.1 mg/kg estimated in the 5-hydroxytryptophan pot entiation test. Maximal inhibition of monoamine oxidase-A (MAO-A) was obser ved by 0.5 h after dosing, suggesting rapid transport to brain. Inhibition in brain was maintained for several hours, followed by a gradual reversal w ith a half-time of 7.2 h. Brain levels of parent compound were higher than plasma levels at all times after dosing. No significant inhibition of MAO-B was observed. After preincubation of MAO with 2614W94 at 37 degrees C, the inhibition was reversed by dialysis. Concentrations of serotonin, norepine phrine, and dopamine were clearly elevated in brains oi rats after single o ral doses, whereas levels of MAO metabolites were decreased. In a rat model designed to show blood pressure elevations in response to a threshold dose of orally administered tyramine, 2614W94 compared well with moclobemide, a n MAO-A selective inhibitor that has not been associated with problems rela ting to dietary tyramine. The two stereoisomers of 2614W94 were both potent MAO-A inhibitors. In vitro and in vivo properties of 2614W94 suggest that this compound and its close analogs are among the most potent MAO-A inhibit ors known and that they may have therapeutic potential as safe new antidepr essant/anxiolytic agents. Drug Dev. Res. 45:1-9, 1998. (C) 1998 Wiley-Liss, Inc.