A novel MDMA analogue, UWA-101, that lacks psychoactivity and cytotoxicity, enhances L-DOPA benefit in parkinsonian primates

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dc.contributor.authorJohnston, Tom
dc.contributor.authorMillar, Zak A
dc.contributor.authorHuot, Philippe
dc.contributor.authorWagg, Keith
dc.contributor.authorTheile, Sherri
dc.contributor.authorSalomonczyk, Danielle
dc.contributor.authorYong-Kee, Christopher J
dc.contributor.authorGandy, Michael N
dc.contributor.authorMcIldowie, Matthew
dc.contributor.authorLewis, Katie
dc.contributor.authorGomez-Ramirez, Jordie
dc.contributor.authorLee, Joohyung
dc.contributor.authorFox, Susan H
dc.contributor.authorMartin-Iverson, Mathew
dc.contributor.authorNash, Joanne E
dc.contributor.authorPiggott, Matthew J
dc.contributor.authorBrotchie, Jonathan M
dc.date.accessioned2015-12-10T23:00:44Z
dc.date.issued2012
dc.date.updated2016-02-24T10:25:18Z
dc.description.abstractTreatment of Parkinson's disease with dopaminergic agents, such as L-DOPA, is frequently compromised by disabling side effects, particularly dyskinesia and a shortening in duration of antiparkinsonian action. Studies in animal models and anecdotal evidence from a patient with Parkinson's disease show that the illicit drug ecstasy (MDMA) can alleviate these side effects, though with many drawbacks (e.g., psychoactivity). MDMA itself thus has little therapeutic potential. On the basis of known structure-psychoactivity relationships, we designed a series of α-substituted MDMA analogues, one of which, bearing an α-cyclopropyl substituent (UWA-101), enhanced the quality of L-DOPA actions in animal models. Indeed, UWA-101 was more effective than MDMA.Unlike MDMA, UWA-101 did not reduce viability of serotonergic cells, exhibit psychoactive properties, or reduce food intake, and did not substitute for MDMA in drug discrimination assays. UWA-101 displayed a unique receptor/transporter binding profile relative to MDMA, with a >5-fold decrease in affinity for NET and 5-HT2A receptors and a 10-fold increase in affinity for DAT. Furthermore, in a functional reuptake assay, UWA-101 inhibited both 5-HT and dopamine reuptake, while having no effect on the reuptake of noradrenaline. UWA-101 is the first selective DAT/SERT inhibitor described with comparable affinities for these two sites. These data identify a new class of therapeutic in Parkinson's disease and highlight the potential benefits of studying illicit drugs that in themselves would never be considered safe for longterm therapy.
dc.identifier.issn0892-6638
dc.identifier.urihttp://hdl.handle.net/1885/61476
dc.publisherFederation of American Societies for Experimental Biology
dc.sourceFASEB Journal
dc.subjectKeywords: 1 (2 methoxyphenyl) 4 (4 phthalimidobutyl)piperazine; 1 [2 (benzhydryloxy)ethyl] 4 (3 phenylpropyl)piperazine; 1,2,3,5 tetrahydro 5 methyl 1 (3 pyridylcarbamoyl)pyrrolo[2,3 f]indole; 1,2,3,6 tetrahydro 1 methyl 4 phenylpyridine; 2 (benzo[d][1,3]dioxol 5 y Drug of abuse; Ecstasy; Methylenedioxymethamphetamine; Translational medicine
dc.titleA novel MDMA analogue, UWA-101, that lacks psychoactivity and cytotoxicity, enhances L-DOPA benefit in parkinsonian primates
dc.typeJournal article
local.bibliographicCitation.issue5
local.bibliographicCitation.lastpage2163
local.bibliographicCitation.startpage2154
local.contributor.affiliationJohnston, Tom, Toronto Western Research Institute
local.contributor.affiliationMillar, Zak A, University of Western Australia
local.contributor.affiliationHuot, Philippe, Toronto Western Research Institute
local.contributor.affiliationWagg, Keith, College of Physical and Mathematical Sciences, ANU
local.contributor.affiliationTheile, Sherri, Univeristy of Toronto at Scarborough
local.contributor.affiliationSalomonczyk, Danielle, University of Toronto
local.contributor.affiliationYong-Kee, Christopher J, Univeristy of Toronto at Scarborough
local.contributor.affiliationGandy, Michael N, University of Western Australia
local.contributor.affiliationMcIldowie, Matthew, University of Western Australia
local.contributor.affiliationLewis, Katie, University of Western Australia
local.contributor.affiliationGomez-Ramirez, Jordie, Toronto Western Research Institute
local.contributor.affiliationLee, Joohyung, Toronto Western Research Institute
local.contributor.affiliationFox, Susan H, Toronto Western Hospital, University Health Network
local.contributor.affiliationMartin-Iverson, Mathew, University of Western Australia
local.contributor.affiliationNash, Joanne E, Univeristy of Toronto at Scarborough
local.contributor.affiliationPiggott, Matthew J, University of Western Australia
local.contributor.affiliationBrotchie, Jonathan M, Toronto Western Research Institute
local.contributor.authoremailrepository.admin@anu.edu.au
local.contributor.authoruidWagg, Keith, u3292392
local.description.embargo2037-12-31
local.description.notesImported from ARIES
local.identifier.absfor030401 - Biologically Active Molecules
local.identifier.absseo970103 - Expanding Knowledge in the Chemical Sciences
local.identifier.ariespublicationu4005981xPUB614
local.identifier.citationvolume26
local.identifier.doi10.1096/fj.11-195016
local.identifier.scopusID2-s2.0-84860913121
local.identifier.thomsonID000307553300001
local.identifier.uidSubmittedByu4005981
local.type.statusPublished Version

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