Antidepressant-like actions of DOV 21,947: a "triple" reuptake inhibitor.
DOV 21,947 [(+)-1-(3,4-dichlorophenyl)-3-azabicyclo-[3.1.0]hexane hydrochloride] inhibits the reuptake of [3H]serotonin, [3H]norepinephrine, and [3H]dopamine in human embryonic kidney (HEK) 293 cells expressing the corresponding human recombinant transporters (IC(50) values of 12, 23, and 96 nM, respectively). This compound also inhibits [125I]RTI 55 (3beta-(4-iodophenyl)tropane-2beta-carboxylic acid methyl ester) binding to the corresponding transporter proteins in membranes prepared from these cells (K(i) values of 99, 262, and 213 nM, respectively). DOV 21,947 reduces the duration of immobility in the forced swim test (using rats) with an oral minimum effective dose of 5 mg/kg. This antidepressant-like effect manifests in the absence of significant increases in motor activity at doses of up to 20 mg/kg. DOV 21,947 also produces a dose-dependent reduction in immobility in the tail suspension test, with a minimum effective oral dose of 5 mg/kg. The ability of DOV 21,947 to inhibit the reuptake of three biogenic amines closely linked to the etiology of depression may result in a therapeutic profile different from antidepressants that inhibit the reuptake of serotonin and/or norepinephrine.
Skolnick
Phil
P
DOV Pharmaceutical, Inc., Continental Plaza, 433 Hackensack Avenue, Hackensack, NJ 07601, USA. pskolnick@dovpharm.com
Popik
Piotr
P
Janowsky
Aaron
A
Beer
Bernard
B
Lippa
Arnold S
AS
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001372:Aza Compounds / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D001667:Binding, Competitive / Q000187:drug effects; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000494:pharmacology*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D003042:Cocaine / Q000031:analogs & derivatives* / Q000378:metabolism; D004298:Dopamine / Q000502:physiology; D050483:Dopamine Plasma Membrane Transport Proteins; D004305:Dose-Response Relationship, Drug; D015870:Gene Expression; D019417:Hindlimb Suspension; D006801:Humans; D007457:Iodine Radioisotopes; D008297:Male; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity / Q000187:drug effects; D009419:Nerve Tissue Proteins; D014179:Neurotransmitter Uptake Inhibitors / Q000494:pharmacology*; D009638:Norepinephrine / Q000502:physiology; D050484:Norepinephrine Plasma Membrane Transport Proteins; D051381:Rats; D017208:Rats, Wistar; D012701:Serotonin / Q000502:physiology; D050486:Serotonin Plasma Membrane Transport Proteins; D013550:Swimming; D027981:Symporters / Q000235:genetics / Q000378:metabolism; D014316:Tritium
C474071:1-(3,4-dichlorophenyl)-3-azabicyclo-(3.1.0)hexane hydrochloride; D000928:Antidepressive Agents; D001372:Aza Compounds; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002352:Carrier Proteins; D050483:Dopamine Plasma Membrane Transport Proteins; D007457:Iodine Radioisotopes; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D009419:Nerve Tissue Proteins; D014179:Neurotransmitter Uptake Inhibitors; D050484:Norepinephrine Plasma Membrane Transport Proteins; C493227:SLC6A2 protein, human; C493230:SLC6A4 protein, human; D050486:Serotonin Plasma Membrane Transport Proteins; C493228:Slc6a2 protein, mouse; C493226:Slc6a2 protein, rat; C493231:Slc6a4 protein, mouse; C493232:Slc6a4 protein, rat; D027981:Symporters; D014316:Tritium; D012701:Serotonin; C069723:2beta-carbomethoxy-3beta-(4-iodophenyl)tropane; D003042:Cocaine; D004298:Dopamine; D009638:Norepinephrine