4.3.5.2 Drugs Interfering with Catecholamine Metabolism
This group of drugs consists primarily of compounds that block the enzyme monoamine
oxidase (MAO). While useful as hypotensive and antidepressant drugs, their side effects
can be serious. We discuss them briefly as enzyme inhibitors in chapter 8.
4.3.5.3 Drugs Interfering with Catecholamine Storage and Reuptake
These drugs can act in two different ways. The Rauwolfia alkaloid reserpine (3.1) and
related natural or semisynthetic compounds interfere with the membranes of synaptic
vesicles and deplete nerve endings of NE and dopamine (and, incidentally, of serotonin
in serotonergic neurons). The resulting decrease in available neurotransmitter results in
hypotension as well as in sedation. It seems that NE reuptake into the vesicles is also
impaired. Because more effective drugs are available, reserpine is seldom if ever used,
and only as a hypotensive agent. Interestingly, however, reserpine had been used for
centuries in India and is one of the few examples of an “ethnopharmacologic” agent
successfully introduced into Western therapeutics.
(+)-Amphetamine (4.37, phenylisopropylamine) has been historically used as a
mood elevator and psychomotor stimulant by persons who must stay awake (truck-
drivers, students), and it is still illicitly used as an appetite suppressant (anorectic) and
as a mood-altering drug. A specific amphetamine-binding site related to anorectic activ-
ity has been described in the hypothalamus. In addition, amphetamines have multiple
neuronal effects: they inhibit neurotransmitter reuptake, increase transmitter release, are
directαagonists, and may also inhibit the enzyme monoamine oxidase. Amphetamine
is, however, a dangerous drug. In high doses, or when given intravenously (as “speed,”
the street drug), it can cause symptoms of paranoid psychosis by releasing dopamine
in the CNS. It also has cardiovascular effects, and its use is followed by a depressive
“letdown” period.
The second mode of interference with neurotransmitter storage is the prevention of
neurotransmitter release from storage vesicles. Compounds acting in this way are known
as adrenergic neuronal blocking agents. Among these are guanidine compounds such as
guanethidine (4.38), and quaternary ammonium compounds such as bretylium (4.39).
226 MEDICINAL CHEMISTRY