The development of monoamine oxidase (MAO) inhibitors has followed a winding path. At the origin was the finding of E. A. Zeller that iproniazid, a hydrazine derivative designed to improve the tuberculostatic action of isoniazid, caused potent inhibition of MAO in vitro and in vivo. The inhibitor also exerted in vivo activity in the brain, subsequent pharmacological research indicating that this inhibition led to changes of cerebral functions [1]. Although the drug had no overt behavioral effects in animals when given alone, it modified the action of reserpine, one of the first modern psychotropic drugs. Thus, administration of iproniazid prior to reserpine unexpectedly antagonized the decreases in locomotor activity and in 5-hydroxy-tryptamine (5 HT) levels induced by reserpine in the brain, the animals sometimes even showing locomotor stimulation [1]. Since one serious side effect of reserpine in man was known to be mental depression, the antagonism of reserpine by iproniazid hinted at the possibility that this drug might be of use in the treatment of mood disorders. However, the actual breakthrough for the development of iproniazid as an antidepressant came from clinical observations. Various investigators had reported psychostimulant side effects of the MAO inhibitor in patients with tuberculosis and other chronic diseases.

The new generation of monoamine oxidase inhibitors.

The actions of many drugs involve enzyme inhibition. This is exemplified by the inhibitors of monoamine oxidases (MAO) and the cholinsterases (ChE) that have been used for several pharmacological purposes. This review describes key principles and approaches for the reliable determination of enzyme activities and inhibition as well as some of the methods that are in current use for such studies with these two enzymes. Their applicability and potential pitfalls arising from their inappropriate use are discussed. Since inhibitor potency is frequently assessed in terms of the quantity necessary to give 50% inhibition (the IC50 value), the relationships between this and the mode of inhibition is also considered, in terms of the misleading information that it may provide. Incorporation of more than one functionality into the same molecule to give a multi-target-directed ligands (MTDLs) requires careful assessment to ensure that the specific target effects are not significantly altered and that the kinetic behavior remains as favourable with the MTDL as it does with the individual components. Such factors will be considered in terms of recently developed MTDLs that combine MAO and ChE inhibitory functions.

https://www.mdpi.com/1420-3049/22/7/1192/pdf

J Fowler Christopher

Papers

Time-dependent inhibition of monoamine oxidase by β-phenethylamine