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

Summary 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 × 10−8M and 2·5 × 10−7M respectively. Higher concentrations were required to inhibit tyramine oxidation whilst benzylamine oxidation was inhibited only at concentrations above 10−5M. 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.