Synthesis and biological evaluation of 2-(4-fluorophenoxy)-2-phenyl-ethyl piperazines as serotonin-selective reuptake inhibitors with a potentially improved adverse reaction profile
by
Dorsey JM, Miranda MG, Cozzi NV, Pinney KG.
Department of Chemistry and Biochemistry
and The Center for Drug Discovery,
Baylor University, Waco, TX 76798-7348, USA.
Bioorg Med Chem. 2004 Mar 15;12(6):1483-91.


ABSTRACT

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.
SSRIs
Viagra
Dosage
Serotonin
Bupropion
Yohimbine
Fluoxetine
Amineptine
Nitric oxide
Moclobemide
Testosterone
Phentolamine
Drugs and sex
Phophodiesterase
Designer aphrodisiacs
Viagra: clinical efficacy
Antidepressants and sex
SSRIs and disinhibited libido?
Dopamine, serotonin and sex
SSRIs and sexual functioning
Are SNRIs more effective than SSRIs?


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