title: A novel MDMA analogue, UWA-101, that lacks psychoactivity and cytotoxicity, enhances L-DOPA benefit in parkinsonian primates.
abstract: Treatment 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-HT(2A) 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 long-term therapy.
authors.affiliation: Toronto Western Research Institute, 399 Bathurst St, MC-11-419, Toronto, ON, Canada.
authors.forename: Tom H
authors.initials: TH
authors.lastname: Johnston
authors.forename: Zak
authors.initials: Z
authors.lastname: Millar
authors.forename: Philippe
authors.initials: P
authors.lastname: Huot
authors.forename: Keith
authors.initials: K
authors.lastname: Wagg
authors.forename: Sherri
authors.initials: S
authors.lastname: Thiele
authors.forename: Danielle
authors.initials: D
authors.lastname: Salomonczyk
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Yong-Kee
authors.forename: Michael N
authors.initials: MN
authors.lastname: Gandy
authors.forename: Matthew
authors.initials: M
authors.lastname: McIldowie
authors.forename: Katie D
authors.initials: KD
authors.lastname: Lewis
authors.forename: Jordi
authors.initials: J
authors.lastname: Gomez-Ramirez
authors.forename: Joohyung
authors.initials: J
authors.lastname: Lee
authors.forename: Susan H
authors.initials: SH
authors.lastname: Fox
authors.forename: Mathew
authors.initials: M
authors.lastname: Martin-Iverson
authors.forename: Joanne E
authors.initials: JE
authors.lastname: Nash
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Piggott
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Brotchie
mesh_terms: D000818:Animals; D000978:Antiparkinson Agents / Q000627:therapeutic use*; D052117:Benzodioxoles / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D004357:Drug Synergism; D007980:Levodopa / Q000627:therapeutic use*; D008297:Male; D008744:Methylamines / Q000627:therapeutic use*; D018817:N-Methyl-3,4-methylenedioxyamphetamine / Q000031:analogs & derivatives* / Q000627:therapeutic use; D010300:Parkinson Disease / Q000188:drug therapy*; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D000978:Antiparkinson Agents; D052117:Benzodioxoles; D008744:Methylamines; C579241:N-methyl-1-cyclopropyl-1-piperonylmethylamine; D007980:Levodopa; D018817:N-Methyl-3,4-methylenedioxyamphetamine