Antidepressant-like actions of DOV 21,947: a “triple” reuptake inhibitor

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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 (3β-(4-iodophenyl)tropane-2β-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.