The novel triple reuptake inhibitor JZAD-IV-22 exhibits an antidepressant pharmacological profile without locomotor stimulant or sensitization properties

Barbara J. Caldarone, Neil E. Paterson, Jia Zhou, Daniela Brunner, Alan P. Kozikowski, Koen G.C. Westphal, Gerdien A.H. Korte-Bouws, Jolanda Prins, S. Mechiel Korte, Berend Olivier, Afshin Ghavami

Research output: Contribution to journalArticle

19 Scopus citations

Abstract

Triple reuptake inhibitors (TRIs) that block the dopamine transporter (DAT), norepinephrine transporter, and serotonin transporter are being developed as a new class of antidepressant that may have better efficacy and fewer side effects compared with traditional antidepressants. We describe a novel TRI, 2-[4-(4-chlorophenyl)-1-methylpiperidin-3-ylmethylsulfanyl]-1-(3- methylpiperidin-1-yl)-ethanone (JZAD-IV-22), that inhibits all three monoamine transporters with approximately equal potency in vitro. (+/-)-1-(3,4- dichlorophenyl)-3-azabicyclo-[3.1.0]hexane hydrochloride (DOV 216,303), a TRI shown to be an effective antidepressant in a clinical trial, shows reuptake inhibition similar to that of JZAD-IV-22 in vitro. Furthermore, both JZAD-IV-22 and DOV 216,303 increase levels of dopamine, norepinephrine, and serotonin in the mouse prefrontal cortex when administered by peripheral injection. JZAD-IV-22 and DOV 216,303 exhibited antidepressant-like efficacy in the mouse forced-swim and tail-suspension tests at doses that increased neurotransmitter levels. Because development of DAT inhibitors could be hindered by abuse liability, both JZAD-IV-22 and DOV 216,303 were compared in two assays that are markers of abuse potential. Both JZAD-IV-22 and DOV 216,303 partially substituted for cocaine in a drug discrimination assay in rats, and high doses of DOV 216,303 produced locomotor sensitization in mice. JZAD-IV-22 showed no evidence of sensitization at any dose tested. These results demonstrate that JZAD-IV-22 is a TRI with antidepressant-like activity similar to that of DOV 216,303. The striking feature that distinguishes the two TRIs is that locomotor sensitization, a common underlying feature of drugs of abuse, is seen with DOV 216,303 but is completely lacking in JZAD-IV-22. These findings may have implications for the potential for abuse liability in humans.

Original languageEnglish (US)
Pages (from-to)762-770
Number of pages9
JournalJournal of Pharmacology and Experimental Therapeutics
Volume335
Issue number3
DOIs
StatePublished - Dec 1 2010
Externally publishedYes

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ASJC Scopus subject areas

  • Molecular Medicine
  • Pharmacology

Cite this

Caldarone, B. J., Paterson, N. E., Zhou, J., Brunner, D., Kozikowski, A. P., Westphal, K. G. C., Korte-Bouws, G. A. H., Prins, J., Korte, S. M., Olivier, B., & Ghavami, A. (2010). The novel triple reuptake inhibitor JZAD-IV-22 exhibits an antidepressant pharmacological profile without locomotor stimulant or sensitization properties. Journal of Pharmacology and Experimental Therapeutics, 335(3), 762-770. https://doi.org/10.1124/jpet.110.174011