1521-0103/357/3/562–569$25.00 http://dx.doi.org/10.1124/jpet.116.232371 THE JOURNAL OF PHARMACOLOGY AND EXPERIMENTAL THERAPEUTICS J Pharmacol Exp Ther 357:562–569, June 2016 Copyright ª 2016 by The American Society for Pharmacology and Experimental Therapeutics Minireviews Dopamine Reuptake Inhibitors in Parkinson’s Disease: A Review of Nonhuman Primate Studies and Clinical Trials Philippe Huot,1 Susan H. Fox, and Jonathan M. Brotchie The Krembil Institute (P.H., S.H.F., J.M.B.) and Movement Disorder Clinic (P.H., S.H.F.), Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada; and Division of Neurology, University of Toronto, Toronto, Ontario, Canada (P.H., S. Downloaded from H.F.) Received January 21, 2016; accepted April 6, 2016 ABSTRACT Striatal dopamine deficiency is the core feature of the pathology of as they increase synaptic dopamine levels, dopamine transporter jpet.aspetjournals.org Parkinson’s disease (PD), and dopamine replacement with L-3,4- (DAT) inhibitors, whether they are selective or have actions on dihydroxyphenylalanine (L-DOPA) is the mainstay of PD treatment. noradrenaline or serotonin transporters, theoretically represent an Unfortunately, chronic L-DOPA administration is marred by the attractive way to alleviate parkinsonism per se and potentially emergence of dyskinesia and wearing-off. Alternatives to L-DOPA enhance L-DOPA antiparkinsonian action (provided that sufficient for alleviation of parkinsonism are of interest, although none can dopamine terminals remain within the striatum). Several non- match the efficacy of L-DOPA to date. Catechol-O-methyltrans- human primate studies and clinical trials have been performed to ferase and monoamine oxidase inhibitors are currently used to evaluate the potential of DAT inhibitors for PD. In this article, we alleviate wearing-off, but they do not increase “on-time” without review nonhuman primate studies and clinical trials, we summa- at ASPET Journals on September 29, 2021 exacerbating dyskinesia. Alternate approaches to dopamine re- rize the current knowledge of DAT inhibitors in PD, and we placement in parkinsonism generally (and to wearing-off and propose a hypothesis as to how tailoring the selectivity of DAT dyskinesia, specifically) are therefore urgently needed. Inasmuch inhibitors might maximize the benefits of DAT inhibition in PD. Introduction a complex issue (Fox and Lang, 2014), and whether to initiate therapy with a DOPA-sparing approach or L-DOPA has been an ’ Parkinson s disease (PD) is a neurodegenerative disorder in area of intense research recently (Cilia et al., 2014; Gray et al., which striatal dopamine levels are diminished (Hornykiewicz 2014). Therapies for the wearing-off phenomenon remain limited and Kish, 1987). Treatment with the dopamine precursor L-3,4- and essentially consist of inhibiting catechol-O-methyltransferase dihydroxyphenylalanine (L-DOPA) has been the mainstay of PD and MAO-B, the enzymes responsible for dopamine degradation therapy for the past 4 decades (Fahn, 2008). Unfortunately, (Parkinson Study Group, 2005; Rascol et al., 2005). However, chronic therapy with L-DOPA leads to the development of motor it seems to be very difficult to extend the duration of L-DOPA complications, including a shortening of duration of benefit, antiparkinsonian benefit (i.e., alleviate wearing-off) without wearing-off, and abnormal involuntary movements (dyskinesia) exacerbating dyskinesia; when catechol-O-methyltransferase (Hely et al., 2005). and MAO-B inhibitors are used as adjunct therapy, the extra There are several treatment options for early PD, including “on-time” gained is on-time with dyskinesia (Parkinson Study L-DOPA, dopamine agonists, amantadine, and monoamine Group, 2005; Rascol et al., 2005). oxidase type B (MAO-B) inhibitors. Treatment of early PD is Another potential approach to alleviate parkinsonian dis- ability and wearing-off lies in increasing the time spent by This research was supported by the Cure Parkinson Trust and the Krembil dopamine in the synaptic cleft and maximizing its chances of Neuroscience Fund. P.H. was supported by fellowships from the Edmond J. Safra Philanthropic Foundation, the Parkinson Society Canada, and the interaction with postsynaptic dopaminergic receptors; this Canadian Institutes of Health Research. could be achieved by preventing the reuptake of dopamine into 1Current affiliation: Division of Neurology, Department of Pharmacology, Montreal University Health Centre, Montreal, Quebec, Canada. the presynaptic neuron by the dopamine transporter (DAT). dx.doi.org/10.1124/jpet.116.232371. By the same mechanism, blocking dopamine reuptake might ABBREVIATIONS: 5-HT, serotonin; BTS-74,398, 1-([1-(3,4-dichlorophenyl)cyclobutyl]-2-(3-diaminethylaminopropylthio)ethanone; DAT, dopamine transporter; L-DOPA, L-3,4-dihydroxyphenylalanine; GBR-12,909, 1-[2-[bis-(4-fluorophenyl)methoxy]ethyl]-4-(3-phenylpropyl) piperazine dihydrochloride; MAO-B, monoamine oxidase type B; MDMA, 3,4-methylenedioxymethamphetamine; MPTP, 1-methyl-4-phenyl-1,2,3,6- tetrahydropyridine; NAT, noradrenaline transporter; PD, Parkinson’s disease; SERT, serotonin transporter; UWA-101, 2-(1,3-benzodioxol-5-yl)-1- cyclopropyl-N-methylethanamine. 562 Dopamine Reuptake Inhibitors in Parkinson’s Disease 563 also exert an antiparkinsonian action as monotherapy. These selective DAT inhibitors have little effect on L-DOPA antipar- theoretical antiparkinsonian benefits form the rationale un- kinsonian efficacy and L-DOPA–induced dyskinesia. derlying the potential use of DAT inhibitors in PD. Many DAT inhibitors have been identified and span a spectrum of Dual DAT and NAT Inhibitors selectivity for DAT over other monoamine transporters; the pharmacology of these was recently reviewed in detail else- Brasofensine, bupropion, methylphenidate, and nomifen- where (Huot et al., 2015). sine are dual DAT and NAT inhibitors (with a DAT/NAT ratio In this article, we review the literature on selective and between 0.5 and 4; Huot et al., 2015) and have been studied as nonselective DAT inhibitors, their antiparkinsonian effect as potential therapies for PD. monotherapy, and their effects on on-time and dyskinesia as In the MPTP-lesioned marmoset, monotherapy with adjunct therapy. We also propose a hypothesis as to how the brasofensine reversed parkinsonian disability without elicit- pharmacoselectivity of DAT inhibitors might be best tailored ing dyskinesia (Pearce et al., 1995), and adjunct therapy with to maximize benefit in PD. Throughout, we divide the mono- brasofensine enhanced the antiparkinsonian action of low- amine reuptake inhibitors based on their affinity for DATs, dose L-DOPA. Similarly, in the parkinsonian marmoset, mono- noradrenaline transporters (NATs), and serotonin trans- therapy with nomifensine significantly improved parkinso- porters (SERTs). As in a previous article (Huot et al., 2015), nian disability (Hansard et al., 2002b). In contrast, monotherapy we considered that a compound was selective for a transporter with bupropion had no effect on parkinsonian disability when its affinity for that transporter was greater than 10-fold (Hansard et al., 2002b). Therefore, on balance, it seems that Downloaded from its affinity for that of the other transporters. dual DAT/NAT inhibitors can be effective as antiparkinsonian Here, we review preclinical studies performed in the 1- molecules when administered as monotherapy to the parkinso- methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)–lesioned nian monkey and, based on one single study, they appear nonhuman primate and clinical trials performed with pa- effective at enhancing the antiparkinsonian action of low- tients suffering from idiopathic PD (published prior to April dose L-DOPA. However, the nonhuman primate studies have not 2015). Studies performed in the 6-hydroxydopamine–lesioned addressed the important question of combining dual DAT/NAT jpet.aspetjournals.org rat were not included in our review because the vast majority inhibitors to high-dose L-DOPAinparkinsonianmonkeyswith of these studies employed rotational behavior as an endpoint, established dyskinesia. which can be difficult to interpret with respect to parkinson- Unlike selective DAT inhibitors, dual DAT/NAT inhibitors ism and dyskinesia benefits/liability (Marin et al., 2006). The have undergone clinical testing. In a small escalating-dose effects of the drugs discussed in the article are summarized in study, brasofensine did not enhance L-DOPA antiparkinso- Tables 1 and 2. nian action and did not alter L-DOPA–induced dyskinesia severity (Archibald, 2000; Cutler et al., 2000; Frackiewicz at ASPET Journals on September 29, 2021 Selective DAT Inhibitors et al., 2002). In a phase II trial, the administration of brasofensine as monotherapy to patients with recently di- GBR-12,909 (vanoxerine; 1-[2-[bis-(4-fluorophenyl)methoxy] agnosed PD initially improved parkinsonism, but the improve- ethyl]-4-(3-phenylpropyl)piperazine dihydrochloride) and SEP- ment was not maintained after 2 weeks (Yu, 2000). In contrast 228,791 are selective DAT inhibitors (Huot et al., 2015) that with brasofensine, bupropion effectively alleviated parkinson- have been evaluated in the MPTP-lesioned monkey. To date, ism in a small add-on trial but exacerbated dyskinesia sever- neither GBR-12,909 nor SEP-228,791 has been studied in ity in one patient (Goetz et al., 1984). In two small trials, idiopathic PD. monotherapy with nomifensine effectively alleviated parkin- In the MPTP-lesioned common marmoset, acute challenge