A comparison of the pharmacological and biochemical properties of substrate-selective monoamine oxidase inhibitors.

1. M&B 9302, E-250, NSD 2023, and Lilly 51641, substrate-selective inhibitors of monoamine oxidase (MAO), and two non-selective inhibitors of MAO (tranylcypromine and phenelzine) have been compared in the rat for activity in (i) inhibiting rat brain monoamine oxidase in vitro and in vivo using tyramine, 5-hydroxytryptamine (5-HT) and benzylamine as substrates; (ii) increasing brain levels of noradrenaline (NA) and 5-HT and (iii) antagonizing tetrabenazine-induced sedation.2. Concentrations of M&B 9302 and Lilly 51641 required to produce 50% inhibition of 5-HT oxidation by brain mitochondrial MAO were 1.4 x 10(-8)M and 2.5 x 10(-7)M respectively. Higher concentrations were required to inhibit tyramine oxidation whilst benzylamine oxidation was inhibited only at concentrations above 10(-5)M.3. E-250 showed the reverse substrate-selectivity in inhibiting the oxidation of benzylamine at concentrations below that required to inhibit the oxidation of 5-HT. NSD 2023 showed little substrate selectivity in vitro.4. Qualitatively similar results were obtained in vivo, except that NSD 2023 showed more marked substrate-selectivity.5. All the inhibitors except E-250 produced a dose-related rise in brain 5-HT levels. Only phenelzine and Lilly 51641 showed a linear relationship between NA levels and dose.6. All the drugs antagonized, in dose-related fashion, the effects of tetrabenazine in reducing locomotor activity. E-250 and NSD 2023 failed to restore locomotor activity to control levels whilst in high doses the other inhibitors, when given before tetrabenazine, produced a considerable increase in locomotor activity.7. Antagonism of tetrabenazine sedation appears to be correlated with (a) inhibition of the enzyme species that oxidize 5-HT and NA but not with inhibition of the enzyme species that oxidize benzylamine; (b) the rise in brain 5-HT levels rather than NA levels.