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Drugs that
interfere with the uptake and/or metabolism of
biogenic amines have been used to treat depression
for > 4 decades. Early medications such as
tricyclic antidepressants and monoamine oxidase
inhibitors are effective but possess many side
effects that limit their usefulness. Selective
serotonin reuptake inhibitors (SSRIs) or selective
noradrenaline reuptake inhibitors (SNRIs) are the
results of rational design to find drugs that are
as effective as the tricyclic antidepressants, but
with more selectivity towards a single monoamine
transporter. The SSRI class of drugs, which
includes fluoxetine, paroxetine and sertraline,
were previously viewed as the agents of choice for
treating major depression. Recently, inhibitors of
both serotonin and noradrenaline uptake (‘dual
uptake inhibitors’; SSRI/SNRI such as
venlafaxine, duloxetine and milnacipran) have
gained acceptance in the market. However, neither
the SSRIs nor the SSRI/SNRI are fully satisfactory
due to a delayed onset of action, low rate of
response and side effect that can affect
compliance. An important recent development has
been the emergence of the triple uptake inhibitors
(SSRI/SNRI/selective dopamine reuptake inhibitor),
which inhibit the uptake of all three
neurotransmitters that are most closely linked to
depression: serotonin, noradrenaline and dopamine.
Preclinical studies and clinical trials indicate
that a drug inhibiting the uptake of all three of
these neurotransmitters could produce a more rapid
onset of action and possess greater efficacy than
traditional antidepressants. This review discusses
the evolution of biogenic amine-based therapies,
the emerging strategies involved in the design and
synthesis of novel triple uptake inhibitors as
antidepressants and the therapeutic potential of
triple uptake inhibitors.
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