title: A comparison of the pharmacological and biochemical properties of substrate-selective monoamine oxidase inhibitors.
abstract: 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.
mesh_terms: D000588:Amines / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002090:Butyrophenones / Q000494:pharmacology; D003201:Computers; D003521:Cyclopropanes / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D008928:Mitochondria / Q000378:metabolism; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D009025:Morpholines / Q000494:pharmacology; D009043:Motor Activity / Q000187:drug effects; D009638:Norepinephrine / Q000378:metabolism; D010624:Phenelzine / Q000494:pharmacology; D010636:Phenols / Q000494:pharmacology; D011437:Propylamines / Q000494:pharmacology; D051381:Rats; D012701:Serotonin / Q000378:metabolism; D013747:Tetrabenazine / Q000037:antagonists & inhibitors; D013997:Time Factors; D014050:Toluene / Q000494:pharmacology; D014191:Tranylcypromine / Q000494:pharmacology; D014439:Tyramine / Q000494:pharmacology
chemical_list: D000588:Amines; D002090:Butyrophenones; D003521:Cyclopropanes; D008996:Monoamine Oxidase Inhibitors; D009025:Morpholines; D010636:Phenols; D011437:Propylamines; D012701:Serotonin; C001907:NSD 2023; D014191:Tranylcypromine; D014050:Toluene; D010624:Phenelzine; D009638:Norepinephrine; D014439:Tyramine; D013747:Tetrabenazine