Monoamine oxidase inhibition.

Introduction The discovery that inhibitors of monoamine oxidase (EC 1.4.3.4.; MAO) are antidepressants (see [ l ] for a review) has resulted in the synthesis of large numbers of inhibitors, several of which have proved to be valuable in clinical use. Such work was given added impetus when it was recognized that there are two monoamine oxidases in most mammalian tissues, MAO-A and MAO-B, with different substrate and inhibitor specificities. 5-Hydroxytryptamine (5-HT; also known as serotonin) is a preferred substrate for MAO-A and the trace amine 2-phenethylamine is a preferred substrate for MAO-B. Both enzymes from human brain catalyse the oxidation of dopamine, noradrenaline and tyramine (see [2,3] for reviews). Inhibitors of MAO-A have been shown to be effective antidepressants (see [ l]), whereas inhibitors of MAO-B appear to be of value in the treatment of Parkinson’s disease, either in combination with L-dopa [4] or, perhaps, alone 151. It has also been suggested that at least some inhibitors of MAO-B may be capable of either protecting or rescuing neurons from potentially lethal damage (see [6,7]). A particular problem with the use of MA0 inhibitors as antidepressants has been that they can give rise to strong hypertensive responses following the ingestion of some foods and beverages. This was shown to be a result of the relatively high concentrations of amines, often tyramine, in the ingested material (see [ 1,s101). Because some cheeses are particularly rich in tyramine, this effect has become known as the ‘cheese reaction’. However, many other foods and beverages contain amines which can interact in this way, and because of the nature of some of the foods involved and the lack of any legislation controlling the tyramine contents, the quantities present can be extremely variable (see [%lo]). Although tyramine is a good substrate for both forms of the enzyme, it is only those inhibitors that affect MAO-A that give rise to this reaction. This is because MAO-A predominates in the human intestine and stomach, which are the first lines of defence against ingested amines (see [ 1 11). Since the crystal structures of the MAOs have yet to be determined, information for the design of