Medicinal Chemistry

(Jacob Rumans) #1

orienting the amino group of the substrate and decreasing the energy of the transition
state.
Monoamine oxidase has some important physiological roles:



  1. It inactivates many of the neurotransmitters in the synaptic gap or in the synapse if
    the latter are not protected by synaptic vesicles. The metabolism of NE, DA, 5-HT,
    tyramine, and histamine is thus taken care of by MAO as well as by some other
    enzymes.

  2. It detoxifies exogenous amines and may even help to maintain the blood–brain barrier,
    since it is also localized in the walls of the blood vessels.


8.2.6.1 Monoamine Oxidase Inhibitors


Monoamine oxidase inhibitors (MAOIs) are useful as thymoleptic (antidepressant)
drugs, especially since the action of some of these agents is very rapid, as compared to
the lag period of days or even weeks shown by tricyclic antidepressants. All MAOIs act
by increasing the available concentration of the neurotransmitters NE and 5-HT which,
because they are not metabolized, accumulate in the synaptic gap and exert an increased
postsynaptic effect. The drugs show hypotensive activity as a side effect, and some
MAOIs are used as hypotensive drugs.
There are four structural types of MAOI. These are hydrazines, cyclopropylamines,
propargylamines, and carbolines.


Hydrazines.The hydrazines have only historic significance. The entire group of
MAOIs was discovered through the euphoric side effect of isoniazid (8.36, isonicotinyl-
hydrazide), a successful antituberculotic drug introduced in 1952. Iproniazid (8.37) is
the corresponding isopropyl derivative. All of the hydrazides are highly hepatotoxic,
and are no longer available.


Cyclopropylamines.Tranylcypromine (8.38) (trans-phenyl-cyclopropylamine) can be
regarded as a ring-closed derivative of amphetamine, and therefore provides rapid stimu-
lation as well as protracted effect. Like all MAOI drugs, it can produce severe or even fatal
hypertensive crises if taken together with foods containing tyramine, such as cheese.
Preventing the destruction of such a pressor amine produces a sudden increase in blood
pressure, which is especially dangerous in individuals exhibiting high blood pressure.
Therefore, depressive patients taking tranylcypromine must practice diet control and
avoid tyramine-containing foods. Reversible MAOIs do not show this “cheese effect.”


498 MEDICINAL CHEMISTRY

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