title: The novel triple reuptake inhibitor JZAD-IV-22 exhibits an antidepressant pharmacological profile without locomotor stimulant or sensitization properties.
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.
authors.affiliation: PsychoGenics, Inc, 765 Old Saw Mill River Rd, Tarrytown, New York 10591, USA. barbara.caldarone@psychogenics.com
authors.forename: Barbara J
authors.initials: BJ
authors.lastname: Caldarone
authors.forename: Neil E
authors.initials: NE
authors.lastname: Paterson
authors.forename: Jia
authors.initials: J
authors.lastname: Zhou
authors.forename: Daniela
authors.initials: D
authors.lastname: Brunner
authors.forename: Alan P
authors.initials: AP
authors.lastname: Kozikowski
authors.forename: Koen G C
authors.initials: KG
authors.lastname: Westphal
authors.forename: Gerdien A H
authors.initials: GA
authors.lastname: Korte-Bouws
authors.forename: Jolanda
authors.initials: J
authors.lastname: Prins
authors.forename: S Mechiel
authors.initials: SM
authors.lastname: Korte
authors.forename: Berend
authors.initials: B
authors.lastname: Olivier
authors.forename: Afshin
authors.initials: A
authors.lastname: Ghavami
mesh_terms: D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001372:Aza Compounds / Q000009:adverse effects / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000166:cytology; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000009:adverse effects / Q000494:pharmacology; D003042:Cocaine / Q000494:pharmacology; D003342:Corpus Striatum / Q000166:cytology; D003863:Depression / Q000517:prevention & control; D004192:Discrimination, Psychological; D004298:Dopamine / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D019417:Hindlimb Suspension; D007031:Hypothalamus / Q000166:cytology; D008124:Locomotion / Q000187:drug effects*; D008297:Male; D051379:Mice; D008805:Mice, Inbred A; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D009638:Norepinephrine / Q000378:metabolism; D010880:Piperidines / Q000494:pharmacology* / Q000627:therapeutic use; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012701:Serotonin / Q000378:metabolism; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D013550:Swimming; D013574:Synaptosomes / Q000187:drug effects / Q000378:metabolism
chemical_list: D018759:Adrenergic Uptake Inhibitors; D000928:Antidepressive Agents; D001372:Aza Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D003042:Cocaine; D004298:Dopamine; D018765:Dopamine Uptake Inhibitors; D014179:Neurotransmitter Uptake Inhibitors; D009638:Norepinephrine; D010880:Piperidines; D012701:Serotonin; D017367:Selective Serotonin Reuptake Inhibitors; C474071:1-(3,4-dichlorophenyl)-3-azabicyclo-(3.1.0)hexane hydrochloride; C555558:2-(4-(4-chlorophenyl)-1-methylpiperidin-3-ylmethylsulfanyl)-1-(3-methylpiperidin-1-yl)-ethanone