Monoamine oxidase physiological activity

The first two antidepressants, iproniazid and imipramine, were developed in the same decade. They were shown to reverse the behavioural and neurochemical effects of reserpine in laboratory rodents, by inhibiting the inactivation of these monoamine transmitters (Leonard, 1985). Iproniazid inhibits MAO (monoamine oxidase), an enzyme located in the presynaptic neuronal terminal which breaks down NA, 5-HT and dopamine into physiologically inactive metabolites. Imipramine inhibits the reuptake of NA and 5-HT from the synaptic cleft by their transporters. Therefore, both of these drugs increase the availability of NA and 5-HT for binding to postsynaptic receptors and, therefore, result in enhanced synaptic transmission. Conversely, lithium, the oldest but still most frequently used mood stabiliser (see below), decreases synaptic NA (and possibly 5-HT) activity, by stimulating their reuptake and reducing the availability of precursor chemicals required in the biosynthesis of second messengers. 

Adler LE, Hoffer LD, Wiser A, et al Normalization of auditory physiology by cigarette smoking in schizophrenic patients. Am J Psychiatry 150 1856-1861, 1993 Adolfsson R, Gottfries GG, Oreland L, et al Reduced levels of catecholamines in the brain and increased activity of monoamine oxidase in platelets in Alzheimer s disease therapeutic implications, in Alzheimer s Disease Senile Dementia and Related Disorders [Ageing, Vol 7). Edited by Katzman R, Terry RD, Bick KL. New York, Raven, 1978, pp 441-451... 

The harmala alkaloids harmaline (368 X = NH) and harmi.ne (369 X = NH) are active reversible inhibitors of monoamine oxidase (MAO). Benzo[ Jthiophene analogs of harmaline (368 X = S) and harmine (369 X = S), when tested in vitro as inhibitors of rat liver MAO, showed that (368 X = S) was 50 times more potent than harmaline, but (369 X = NH or S) were equivalent in potency. The replacement of the indolic nitrogen by sulfur greatly increased the lipid solubility of the molecule, which was reflected in the physiological disposition of the two analogs. 

Nimmo-Smith, R.H. and Raison, C.G. (1968) Monoamine oxidase activity of Schistosoma mansoni. Comparative Biochemistry and Physiology C 62, 403—416. 

The excretion of amines is unusual in animals. Amines are highly toxic and one method employed by vertebrates to detoxify them is via monoamine oxidase, an enzyme which has been detected in H. diminuta (569). Amines can arise from the decarboxylation of the appropriate amino acid, e.g. glycine and alanine can give rise to methylamine and ethylamine, respectively. Another possible source of amines may be the reduction of azo or nitro compounds (39) and azo- and nitro-reductase activity has been reported from M. expansa (180, 181). Furthermore, the physiologically active amines octopamine, dopamine, adrenalin and serotonin (5-hydroxytryptamine) have been demonstrated in cestodes (283, 296, 435, 681, 682, 758, 859), where they probably function predominantly as neurotransmitters (see Chapter 2). 

One wonders how peoples in primitive societies, with no knowledge of chemistry or physiology, ever hit upon a solution to the activation of an alkaloid by a monoamine oxidase inhibitor. 

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