Antidepressant-like effects of novel triple reuptake inhibitors, PRC025 and PRC050

Amanda M. Shaw, Mona Boules, Yiqun Zhang, Katrina Williams, Jessica Robinson, Paul R. Carlier, Elliott Richelson

Research output: Contribution to journalArticle

45 Scopus citations

Abstract

Most currently prescribed antidepressants act by selectively increasing the synaptic availability of serotonin or norepinephrine, or through action on both serotonin and norepinephrine. However, most therapies require several weeks of treatment before improvement of symptoms is observed and not all patients respond to antidepressant treatment. One strategy that has emerged in new antidepressant development is the use of triple reuptake inhibitors, which inhibit reuptake of serotonin, norepinephrine, and dopamine. These compounds have been hypothesized to have a more rapid onset of activity and better efficacy over single or dual reuptake inhibitor antidepressants in part due to the addition of the dopamine component. We have developed novel compounds that are analogs of venlafaxine, of which two, racemic PRC025 ((2SR, 3RS)-N,N-dimethyl-3-cyclohexyl-3-hydroxy-2-(2′-naphthyl)propylamine) and PRC050 ((2RS,3RS)-N-methyl-3-hydroxy-2-(2′-naphthyl)-3-phenylpropylamine), are highly potent at human serotonin, norepinephrine, and dopamine transporters and inhibit the reuptake of serotonin, norepinephrine, and dopamine into rat brain synaptosomes. These compounds were tested in animal models used to evaluate potential antidepressants: the forced swim test in rats and the tail suspension test in mice. In the forced swim test, both PRC025 and PRC050 reduced the time spent immobile and increased the time spent swimming, comparable to the effects seen with imipramine, a tricyclic antidepressant. In addition, both PRC025 and PRC050 were effective in reducing the time spent immobile in the tail suspension test, again with effects comparable to imipramine. Therefore it appears that our compounds may possess antidepressant activity and represent a new class of triple reuptake inhibitors.

Original languageEnglish (US)
Pages (from-to)30-36
Number of pages7
JournalEuropean Journal of Pharmacology
Volume555
Issue number1
DOIs
StatePublished - Jan 19 2007

Keywords

  • Antidepressant
  • Dopamine
  • Norepinephrine
  • Reuptake inhibitor
  • Serotonin

ASJC Scopus subject areas

  • Pharmacology

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    Shaw, A. M., Boules, M., Zhang, Y., Williams, K., Robinson, J., Carlier, P. R., & Richelson, E. (2007). Antidepressant-like effects of novel triple reuptake inhibitors, PRC025 and PRC050. European Journal of Pharmacology, 555(1), 30-36. https://doi.org/10.1016/j.ejphar.2006.10.004