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

DOV 21,947 [(+)-l-(3,4-dichlorophenyl)-3-azabicyclo-[3.1.0]hexane hydrochloride] inhibits the reuptake of [(3)H]serotonin, [(3)H]norepinephrine, and [(3)H]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 [(125)I] 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. (C) 2003 Elsevier Science B.V. All rights reserved.