functions also act as antidepressants, as will be shown later. Thus, it is likely that
endogenous depression is a biologically heterogeneous syndrome; a single neurotrans-
mitter hypothesis explaining the mode of action of all antidepressant drugs is not
currently feasible.
In the 1970s and 1980s, the tricyclic antidepressants dominated the clinical manage-
ment of depression. Given the somewhat distasteful and unpopular (in the lay press and
movies) nature of frontal lobotomies in the 1950s and ECT (electroconvulsive therapy)
in the 1960s, the molecular approach of tricyclic antidepressants seemed downright civ-
ilized. Given their widespread use (and misuse), they were sometimes simply referred
to as the “tricyclics.” However, it is important to observe that, like the benzodiazepine
molecule (section 4.7.5), the tricyclic moiety is a privileged structure, with a number of
successful molecules having this tricyclic structure. Antihistamines, antidopaminergics
(e.g., phenothiazines, chapter 4), anticonvulsants (e.g., carbamazepine, chapter 7), and
perhaps even anti-prion drugs (chapter 9) may also have tricyclic structures. Various
tricyclic drugs have anticholinergic properties, and people who attempt overdoses with
tricyclic drugs experience life-threatening anticholinergic side effects. In addition, tri-
cyclic molecules may also influence brain Zn^2 +metabolism, especially at the level of
the glutamatergic NMDA receptor (section 4.9.3). Recognizing that the interaction
between a drug and its receptor is a precise dance between atoms and molecular frag-
ments, we see that the three-dimensional interplanar orientation of the various rings
is crucial to an appreciation of their varying modes of action. Quantum pharmacology
calculations emphasize this point.
In more recent years the tricyclic antidepressants have lost their position as the
mainstay of therapy for depression and have been gradually supplanted by the selective
serotonin reuptake inhibitors(SSRIs), such as fluoxetine. The tricyclics, however, do
continue to be valuable in the management of chronic pain states such as headache or
neuropathy.
An effect different from that of tricyclic antidepressants has been shown by the
simple salt Li 2 CO 3 , commonly referred to “licarb” or simply as “lithium.” It has been
used since about 1970 in the long-term management of manic-depressive disorder,but
it is not useful in acute mania, since its mood-stabilizing effects are seen only after
8–10 days. The mode of action of Li salts remains to be fully elucidated. Apart from
interferences with transmembrane ion fluxes (via ion channels and pumps), Li+appears
to facilitate membrane depletion of phosphatidylinositol bisphosphates, the principal
lipid substrate used by various receptors in transmembrane signaling; blockade of this
signal transduction pathway impairs the ability of neurons to respond to the activation
of neurotransmitter receptors. Lithium may also affect the GTP-binding proteins respon-
sible for signal transduction initiated by the formation of the agonist–receptor complex.
Based upon mechanisms such as these, various reports have claimed that Li+acceler-
ates catecholamine reuptake, stimulates NE turnover, and inhibits NE release—all of
which are in direct opposition to TCA activities.
4.4 DOPAMINE AND THE DOPAMINERGIC RECEPTORS
Dopamine (3,4–dihydroxyphenyl-β-ethylamine, DA) (4.34) is a catecholamine inter-
mediate in the biosynthesis of NE and epinephrine. There are several very important
238 MEDICINAL CHEMISTRY