The tricyclic antidepressants (TCAs) were originally designed to improve upon the efficacy and side effect profile of the phenothiazine class of antipsychotics. Their pharmacological spectrum was quite well understood in that these compounds interact with multiple brain neurotransmitter systems. The TCAs inhibit reuptake of monoamine neurotransmitters (dopamine (DA), 5HT, and NE) increasing their levels and function in the brain. TCAs include imipramine, desipramine, nortriptyline, amitriptyline, clomipramine, and doxepin (Figure 5). These compounds also interact with a variety of biological targets like muscarinic receptors, complicating their pharmacology and contributing to side effects such as orthostasis, dry mouth, and constipation. Clomipramine is the most effective TCA for panic disorder, OCD, and SAD87 but more selective reuptake inhibitors have displaced the use of the tricyclics due to their improved side effect profile.
The origin of the first SSRIs, fluoxetine, resides in the early observation that diphenhydramine blocked monoamine uptake.88 Preparation and testing of analogs of diphenhydramine led to the identification of nisoxetine, which was over 500-fold more selective for NET. Additional SAR studies around the phenoxy substituent ultimately led to the discovery of the 4-trifluoromethyl derivative, fluoxetine. The subtle change in phenoxy substitution appears to be independent of the electronic nature of the substituent since the 4-chloro analog is approximately 10-fold less active and marginally selective for 5HT uptake, whereas the 4-methoxy derivative is only fourfold less active and almost 20-fold more selective for SERT (Figure 6).
Other SSRIs in clinical use are paroxetine, sertraline, citalopram, and fluvoxamine89 (Figure 6). Like fluoxetine, all these compounds have phenyl rings flanking a basic amine moiety except for fluvoxamine, which has only a single 4-trifluoromethyl substituted phenyl ring. The SSRIs emerged as the drugs of choice for the treatment of depression
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