title: In-vitro and in-vivo characterization of JNJ-7925476, a novel triple monoamine uptake inhibitor.
abstract: Triple reuptake inhibitors, which block the serotonin transporter (SERT), norepinephrine transporter (NET) and dopamine transporter (DAT) in the central nervous system have been described as therapeutic alternatives for classical selective serotonin reuptake inhibitors, with advantages due to their multiple mechanisms of action. JNJ-7925476 (trans-6-(4-ethynylphenyl)-1,2,3,5,6,10b-hexahydropyrrolo[2,1-a]isoquinoline) is a selective and potent inhibitor of the SERT, NET, and DAT (K(i)=0.9, 17 and 5.2 nM, respectively). Following subcutaneous dosing in rat, JNJ-7925476 was rapidly absorbed into the plasma, and drug concentrations in the brain tracked with those in the plasma but were 7-fold higher. The ED(50) values for JNJ-7925476 occupancy of the SERT, NET, and DAT in rat brain were 0.18, 0.09 and 2.4 mg/kg, respectively. JNJ-7925476 (0.1-10 mg/kg, s.c.) rapidly induced a robust, dose-dependent increase in extracellular serotonin, dopamine, and norepinephrine levels in rat cerebral cortex. The compound also showed potent antidepressant-like activity in the mouse tail suspension test (ED(50)=0.3 mg/kg, i.p.). These results demonstrate that JNJ-7925476 is a triple reuptake inhibitor with in-vivo efficacy in biochemical and behavioral models of depression.
authors.affiliation: Department of Neuroscience, Johnson & Johnson Pharmaceutical Research & Development, L.L.C., 3210 Merryfield Row, San Diego, CA 92121, USA.
authors.forename: Leah
authors.initials: L
authors.lastname: Aluisio
authors.forename: Brian
authors.initials: B
authors.lastname: Lord
authors.forename: Ann J
authors.initials: AJ
authors.lastname: Barbier
authors.forename: Ian C
authors.initials: IC
authors.lastname: Fraser
authors.forename: Sandy J
authors.initials: SJ
authors.lastname: Wilson
authors.forename: Jamin
authors.initials: J
authors.lastname: Boggs
authors.forename: Lisa K
authors.initials: LK
authors.lastname: Dvorak
authors.forename: Michael A
authors.initials: MA
authors.lastname: Letavic
authors.forename: Bruce E
authors.initials: BE
authors.lastname: Maryanoff
authors.forename: Nicholas I
authors.initials: NI
authors.lastname: Carruthers
authors.forename: Pascal
authors.initials: P
authors.lastname: Bonaventure
authors.forename: Timothy W
authors.initials: TW
authors.lastname: Lovenberg
mesh_terms: D000818:Animals; D019540:Area Under Curve; D001345:Autoradiography; D001812:Blood-Brain Barrier / Q000187:drug effects; D001923:Brain Chemistry / Q000187:drug effects; D045744:Cell Line, Tumor; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000378:metabolism; D019417:Hindlimb Suspension; D006801:Humans; D007546:Isoquinolines / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D017551:Microdialysis; D009043:Motor Activity / Q000187:drug effects; D014179:Neurotransmitter Uptake Inhibitors / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D011758:Pyrroles / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D050486:Serotonin Plasma Membrane Transport Proteins / Q000378:metabolism; D013237:Stereoisomerism
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D007546:Isoquinolines; D014179:Neurotransmitter Uptake Inhibitors; D011758:Pyrroles; D050486:Serotonin Plasma Membrane Transport Proteins; C530836:trans-6-(4-ethynylphenyl)-1,2,3,5,6,10b-hexahydropyrrolo(2,1-a)isoquinoline