Selective MAO A and B inhibitors: their mechanism of action and pharmacology.
The 14C-selective irreversible "suicide" MAO A (clorgyline, Lilly 51641; M & B 9303) and MAO B inhibitors (deprenyl, AGN 1135 and pargyline) bind to the enzyme active site stoichiometrically mol/mol of enzyme. In the case of the acetylenic inhibitors (clorgyline, deprenyl and pargyline) this binding occurs at the N (5) of the FAD isoalloxazine moiety, the enzyme co-factor. Since the inhibitor binding sites of both enzyme forms are identical, it would appear that enzyme inhibitor selectivity must be related to the presence of different recognition sites near their active sites. Studies of structure-MAO inhibitory relationship have shown that the MAO B recognition site is smaller than the enzyme A site. Considering that MAO A for most part is intraneuronal and its substrates noradrenaline (NA) and serotonin (5-HT) have been implicated in the pathogenesis of depressive illness, it would appear that selective A inhibitors would be more effective as antidepressants. Data presented shows that MAO A inhibitors rather that the B inhibitors potentiate pharmacological and behavioural actions mediated by NA and 5-HT. Furthermore, if down-regulation of beta-adrenergic receptors is involved in the mechanism of action of antidepressants it is interesting that chronic treatment with a selective MAO A (clorgyline) but not MAO B (deprenyl) inhibitor resulted in the reduction of [3H]dihydroalprenolol binding and cyclic AMP response to NA in the rat cortex. Recently similar changes were found in peripheral adrenergic systems. These data support the theory that neuronal MAO A inhibition results in elevation of cytoplasmic and synaptic NA and 5-HT, which mediates pre- and post-synaptic receptor changes.
D000818:Animals; D001679:Biogenic Amines / Q000032:analysis / Q000378:metabolism; D001923:Brain Chemistry / Q000187:drug effects; D006801:Humans; D006948:Hyperkinesis / Q000139:chemically induced; D008995:Monoamine Oxidase / Q000145:classification; D008996:Monoamine Oxidase Inhibitors / Q000494:pharmacology*; D051381:Rats; D017981:Receptors, Neurotransmitter / Q000032:analysis / Q000187:drug effects; D013329:Structure-Activity Relationship
D001679:Biogenic Amines; D008996:Monoamine Oxidase Inhibitors; D017981:Receptors, Neurotransmitter; D008995:Monoamine Oxidase