Selective Serotonin Reuptake Inhibitors
Structurally, the SSRIs differ from the tricyclics, in that the tricyclic system has been taken apart in the center. (This abolishes the center ring, and one ring is moved slightly forward from the tricyclic "all-in-a-row" arrangement.) The net effect is that the jS-arylamine-like grouping is present, as in the tri-cyclics, and the compounds can compete for the substrate-binding site of the serotonin transporter protein (SERT). As in the tricyclics, the extra aryl group can add extra affinity and give favorable competition with the substrate, serotonin.
Many of the dimethylamino tricyclics are, in fact, SSRIs. Because they are extensively N-demethylated in vivo to nor-compounds, which are usually SNERIs, however, the overall effect is not selective. Breaking up the tricyclic system breaks up an anticholinergic pharmacophoric group and gives compounds with diminished anticholinergic effects. Overall, this diminishes unpleasant CNS effects and increases cardiovascular safety. Instead, side effects related to serotonin predominate.
In fluoxetine (Prozac), protonated in vivo, the protonated amino group can H-bond to the ether oxygen electrons, which can generate the j-arylamino-like group, with the other aryl serving as the characteristic "extra" aryl. The ^-isomer is much more selective for SERT than for NET. The major metabolite is the N-demethyl compound, which is as potent as the parent and more selective (SERT versus NET).
Therapy for 2 or more weeks is required for the antidepressant effect. Somatodendritic 5-HT1A autoreceptor de-sensitization with chronic exposure to high levels of 5-HT is the accepted explanation for the delayed effect for this and other serotonin reuptake inhibitors.
To illustrate a difference between selectivity for a SERT and a NET, if the para substituent is moved to the ortho position (and is less hydrophobic, typically), a NET is obtained. This and other SERTs have anxiolytic activity. One of several possible mechanisms would be agonism of 5-HT1A receptors, diminishing synaptic 5-HT. Presumably, synaptic levels of 5-HT might be high in an anxious state.
In the structure of paroxetine (Paxil), an amino group, protonated in vivo could H-bond with the -CH2-O- unshared electrons. A j-arylamine-like structure with an extra aryl group results. The compound is a very highly selective SERT. As expected, it is an effective antidepressant and anxiolytic.
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