Comparative study of pirlindole, a selective RIMA, and its two enantiomersusing biochemical and behavioural techniques

The interaction with monoamine oxidase A (MAO-A) and B has been shown to be sensitive to the absolute configuration of molecules. Therefore, the aim o f this study was to compare the effects of the racemic pirlindole (a select ive and reversible MAO-A inhibitor) and its two enantiomers using biochemic al techniques (in vitro and ex vivo determination of rat brain MAO-A and MA O-B activity) and behavioural models (forced swimming test and reserpine-in duced hypothermia and palpebral ptosis test). In vitro, the MAO-A IC50 of ( +/-)-pirlindole, R-(-)-pirlindole and S-(+)-pirlindole were 0.24, 0.43 and 0.18 mu M, respectively. Ex vivo, their ID50 were 24.4, 37.8 and 18.7 mg/kg i.p. The differences between the three compounds were not significant, wit h a ratio between the two enantiomers [R-(-)/S-(+)] of 2.2 in vitro and 2.0 ex vivo. MAO-B was only slightly inhibited. In the forced swimming test an d the reserpine-induced hypothermia and ptosis model, the three compounds h ad an antidepressant profile. In the forced swimming test, the minimal effe ctive dose ratio between the R-(-) and the S-(+) was again around 2.0. The behavioural observations were thus clearly in accordance,vith the biochemic al data. Behav Pharmacol 1998; 9:731-737 (C) 1998 Lippincott Williams & Wil kins.