Loading…
Synthesis and biological evaluation of 2-(4-fluorophenoxy)-2-phenyl-ethyl piperazines as serotonin-selective reuptake inhibitors with a potentially improved adverse reaction profile
Three new 2-(4-fluorophenoxy)-2-phenyl-ethyl piperazines, 1-(3-chlorophenyl)-4-[2-(4-fluorophenoxy)-2-phenylethyl]-piperazine 7, 1-[2-(4-fluorophenoxy)-2-phenylethyl]-4-(2-methoxyphenyl)-piperazine 8, and 1-[2-(4-fluorophenoxy)-2-phenylethyl]-4-(3-trifluoromethylphenyl)-piperazine 9, modeled after t...
Saved in:
Published in: | Bioorganic & medicinal chemistry 2004-03, Vol.12 (6), p.1483-1491 |
---|---|
Main Authors: | , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
Summary: | Three new 2-(4-fluorophenoxy)-2-phenyl-ethyl piperazines, 1-(3-chlorophenyl)-4-[2-(4-fluorophenoxy)-2-phenylethyl]-piperazine
7, 1-[2-(4-fluorophenoxy)-2-phenylethyl]-4-(2-methoxyphenyl)-piperazine
8, and 1-[2-(4-fluorophenoxy)-2-phenylethyl]-4-(3-trifluoromethylphenyl)-piperazine
9, modeled after the potent antidepressant fluoxetine and coupled with several functionalized piperazines, have been prepared by chemical synthesis as selective serotonin reuptake inhibitors (SSRIs) with a potentially improved adverse reaction profile. Typical SSRIs, although very effective in the treatment of depression, still face the troublesome side effect of sexual dysfunction. A number of pharmacological agents-notably, drugs in the piperazine class-have been used to reverse SSRI-induced sexual dysfunction, and evidence for developing an improved SSRI by coupling a fluoxetine congener with the pharmacophore of a reversal agent holds promise. Preliminary data indicates that the hydrochloride (HCl) salts
10,
11, and
12 each exhibit single-site binding at the site of the serotonin reuptake transporter (SERT). However, each of the three compounds are much less potent than typical SSRIs, showing micromolar (μM) affinity for the SERT with IC
50 values of 1.45 μM, 3.27 μM, and 9.56 μM, respectively. Further biological evaluation of compounds
10,
11, and
12 is needed before definitive conclusions can be made with regard to each compound's potential for use as an SSRI-type candidate which is devoid of sexual side effects. Nevertheless, the initial findings are quite encouraging, thus lending credence to the idea of hybridizing an SSRI congener with that of the pharmacophore of an agent known to reverse or treat SSRI-induced sexual dysfunction.
Graphic |
---|---|
ISSN: | 0968-0896 1464-3391 |
DOI: | 10.1016/j.bmc.2003.12.021 |