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 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.
Dorsey
James M
JM
Department of Chemistry and Biochemistry and The Center for Drug Discovery, Baylor University, Waco, TX 76798-7348, USA.
Miranda
Maria G
MG
Cozzi
Nicholas V
NV
Pinney
Kevin G
KG
D001665:Binding Sites; D001792:Blood Platelets / Q000187:drug effects* / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism*; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D010879:Piperazines / Q000138:chemical synthesis* / Q000494:pharmacology*; D012701:Serotonin; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*
D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D010879:Piperazines; D012701:Serotonin; D050486:Serotonin Plasma Membrane Transport Proteins; D017367:Selective Serotonin Reuptake Inhibitors; C493230:SLC6A4 protein, human