PMID- 15018922
OWN - NLM
STAT- MEDLINE
DCOM- 20041021
LR  - 20221207
IS  - 0968-0896 (Print)
IS  - 0968-0896 (Linking)
VI  - 12
IP  - 6
DP  - 2004 Mar 15
TI  - Synthesis and biological evaluation of 2-(4-fluorophenoxy)-2-phenyl-ethyl 
      piperazines as serotonin-selective reuptake inhibitors with a potentially 
      improved adverse reaction profile.
PG  - 1483-91
AB  - 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 (microM) affinity for the 
      SERT with IC(50) values of 1.45 microM, 3.27 microM, and 9.56 microM, 
      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.
FAU - Dorsey, James M
AU  - Dorsey JM
AD  - Department of Chemistry and Biochemistry and The Center for Drug Discovery, 
      Baylor University, Waco, TX 76798-7348, USA.
FAU - Miranda, Maria G
AU  - Miranda MG
FAU - Cozzi, Nicholas V
AU  - Cozzi NV
FAU - Pinney, Kevin G
AU  - Pinney KG
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - Bioorg Med Chem
JT  - Bioorganic & medicinal chemistry
JID - 9413298
RN  - 0 (Carrier Proteins)
RN  - 0 (Membrane Glycoproteins)
RN  - 0 (Membrane Transport Proteins)
RN  - 0 (Nerve Tissue Proteins)
RN  - 0 (Piperazines)
RN  - 0 (SLC6A4 protein, human)
RN  - 0 (Serotonin Plasma Membrane Transport Proteins)
RN  - 0 (Serotonin Uptake Inhibitors)
RN  - 333DO1RDJY (Serotonin)
SB  - IM
MH  - Binding Sites
MH  - Blood Platelets/*drug effects/metabolism
MH  - Carrier Proteins/*metabolism
MH  - Humans
MH  - Membrane Glycoproteins/*metabolism
MH  - *Membrane Transport Proteins
MH  - Nerve Tissue Proteins/*metabolism
MH  - Piperazines/*chemical synthesis/*pharmacology
MH  - Serotonin
MH  - Serotonin Plasma Membrane Transport Proteins
MH  - Selective Serotonin Reuptake Inhibitors/*chemical synthesis/*pharmacology
EDAT- 2004/03/17 05:00
MHDA- 2004/10/22 09:00
CRDT- 2004/03/17 05:00
PHST- 2003/10/03 00:00 [received]
PHST- 2003/12/18 00:00 [accepted]
PHST- 2004/03/17 05:00 [pubmed]
PHST- 2004/10/22 09:00 [medline]
PHST- 2004/03/17 05:00 [entrez]
AID - S0968089603008824 [pii]
AID - 10.1016/j.bmc.2003.12.021 [doi]
PST - ppublish
SO  - Bioorg Med Chem. 2004 Mar 15;12(6):1483-91. doi: 10.1016/j.bmc.2003.12.021.