Antidepressant-Like Pharmacological Profile of a Novel Triple Reuptake Inhibitor, (1S,2S)-3-(Methylamino)-2-(naphthalen-2- yl)-1-phenylpropan-1-ol (PRC200-SS) Yanqi Liang, Amanda M. Shaw, Mona Boules, Siobhan Briody, Jessica Robinson, Alfredo Oliveros, Eric Blazar, Katrina Williams, Yiqun Zhang, Paul R. Carlier, and Elliott Richelson Neuropsychopharmacology Laboratory, Mayo Foundation for Medical Education and Research and Mayo Clinic, Jacksonville, Florida (Y.L., A.M.S., M.B., S.B., J.R., A.O., E.B., K.W., E.R.); and Virginia Polytechnic Institute and State University, Department of Chemistry, Blacksburg, Virginia (Y.Z., P.R.C.) Received July 16, 2008; accepted August 7, 2008 ABSTRACT Due to the putative involvement of dopaminergic circuits in depression, triple reuptake inhibitors are being developed as a new class of antidepressant, which is hypothesized to produce a more rapid onset and better efficacy than current antidepres- sants selective for serotonin or norepinephrine neurotransmis- sion. (1S,2S)-3-(Methylamino)-2-(naphthalen-2-yl)-1-phenylpro- pan-1-ol (PRC200-SS), a new triple reuptake inhibitor, potently bound to the human serotonin, norepinephrine, and dopamine transporters with K d values of 2.3, 0.63, and 18 nM, respec- tively. Inhibition of serotonin, norepinephrine, and dopamine uptake by PRC200-SS was also shown in cells expressing the corresponding transporter (K i values of 2.1, 1.5, and 61 nM, respectively). In vivo, PRC200-SS dose-dependently de- creased immobility in the forced-swim test in rats and in the tail-suspension test in mice, models predictive of antidepres- sant activity, with effects comparable with imipramine. These results in the behavioral models did not seem to result from the stimulation of locomotor activity. Consistent with the in vitro data and behavioral effects, peripheral administration of PRC200-SS (5 and 10 mg/kg i.p.) significantly increased extra- cellular levels of serotonin and norepinephrine in the medial prefrontal cortex, and of serotonin and dopamine in the core of nucleus accumbens, with reduction of levels of 3,4-dihydroxy- phenylacetic acid, homovanillic acid, and 5-hydroxyindoleace- tic acid compared with levels for saline control. Furthermore, PRC200-SS self-administration, which was used as a marker of abuse liability, was not observed with rats. Therefore, it seems that PRC200-SS may represent a novel triple reuptake inhibitor and possess antidepressant activity. The ability of antidepressants to elevate synaptic levels of biogenic amines, such as serotonin (5-HT), norepinephrine (NE), and dopamine (DA), has long been a cornerstone of the biogenic amine hypothesis of affective illness. This hypothe- sis states in part that depression is a deficit of these amines in the synapse. Whereas evidence accumulated over the years supports the notion that all three of these biogenic amines need to be elevated to treat depression (Skolnick et al., 2003b), only monoamine oxidase inhibitors do so directly (Richelson, 2001). There is considerable evidence linking me- socorticolimbic dopaminergic pathways with depression, es- pecially with the anhedonia and lack of motivation observed in many depressed patients (D’Aquila et al., 2000). Therefore, treating depressed patients with an antidepressant that el- evates synaptic levels of DA, in addition to 5-HT and NE, would directly address a core feature of depression. In addi- tion, such a drug might have a broader spectrum of activity and quicker onset of action (Skolnick et al., 2003b). This work is supported by the Mayo Foundation for Medical Education and Research (Rochester, MN). Y.L. and A.M.S. contributed equally to this study. Article, publication date, and citation information can be found at http://jpet.aspetjournals.org. doi:10.1124/jpet.108.143610. ABBREVIATIONS: 5-HT, serotonin; NE, norepinephrine; DA, dopamine; SSRI, selective serotonin reuptake inhibitor; PRC025, (1S/1R,2S/2R)-1- cyclohexyl-3-(dimethylamino)-2-(naphthalen-2-yl)propan-1-ol; PRC050, (1S/1R,2S/2R)-3-(methylamino)-2-(naphthalen-2-yl)-1-phenylpropan-1- ol; PRC200-SS, (1S,2S)-3-(methylamino)-2-(naphthalen-2-yl)-1-phenylpropan-1-ol; PRC200-RR, (1R,2R)-3-(methylamino)-2-(naphthalen-2-yl)-1- phenylpropan-1-ol; WIN 35428, (-)-2--carbomethoxy-3--(4-fluorophenyl)tropane 1,5-napthalenedisulfonate; NIMH, National Institute of Mental Health; PDSP, Psychoactive Drug Screening Program; mPFC, medial prefrontal cortex; NA, nucleus accumbens; AUC, area under the curve; ANOVA, analysis of variance; DOPAC, 3,4-dihydroxyphenylacetic acid; HVA, homovanillic acid; 5-HIAA, 5-hydroxyindoleacetic acid; DOV 21,947, (+)-1-(3,4-dichlorophenyl)-3-azabicyclo-[3.1.0]hexane hydrochloride; DOV 102,677, (1S,5R)-1-(3,4-dichlolrophenyl)-3-azabicyclo(3.1.0)hexane. 0022-3565/08/3272-573–583$20.00 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS Vol. 327, No. 2 Copyright © 2008 by The American Society for Pharmacology and Experimental Therapeutics 143610/3395854 JPET 327:573–583, 2008 Printed in U.S.A. 573 at ASPET Journals on November 4, 2016 jpet.aspetjournals.org Downloaded from