The ^-isomer of fluvoxamine (Luvox) (shown) can fold after protonation to the jS-arylamine-like grouping. Here, the "extra" hydrophobic group is aliphatic.
Citalopram (Celexa) is a racemic mixture and is very SERT selective. The N-monodemethylated compound is slightly less potent but is as selective. The aryl substituents are important for activity. The ether function is important and probably interacts with the protonated amino group to give a suitable shape for SERT binding.
Selective Norepinephrine Reuptake Inhibitors
The discussion of fluoxetine opened the subject of SNERIs. That is, movement of a para substituent of fluoxetine (and relatives) to an ortho position produces a SNERI.
Nisoxetine is a SNERI and is an antidepressant. Most activity resides in the ^-isomer.
Most of the activity of reboxetine resides in the S,S-isomer (The marketed compound is RR and SS.) It is claimed to be superior to fluoxetine in severe depression. It is marketed in Europe. At least three tricyclic compounds, desipramine, nortriptyline, and the technically tetracyclic maprotiline are SNERIs. They, of course, have typical characteristic TCA side effects but lower anticholinergic and H1-antihistaminic (sedative) effects than dimethyl compounds. SNERIs are clinically effective antidepressants.
It would be expected that in the case of SNERIs, a2 presynaptic receptors would be desensitized, after which sustained NE transmission would be via one or more postsynaptic receptors; a1, ff1, and ff2 receptors are possibilities.
Newer (Nontricyclic) Nonselective 5-HT And NE Reuptake Inhibitors
Presently, one such compound is clinically used in the United States.
The structure and activity of venlafaxine (Effexor) are in accord with the general SARs for the group. As expected, it is an effective antidepressant. Venlafaxine is a serotonin-nor-epinephrine reuptake inhibitor (SNRI).
Selective Serotoninergic Reuptake Inhibitors and 5-HT2A Antagonists
The SSRIs and 5-HT2A antagonists are represented by trazodone (Desyrel) and nefazodone (Serzone).
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