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

FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology
Tom H JohnstonJonathan M Brotchie

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 n...Continue Reading

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Citations

Jul 6, 2012·The European Journal of Neuroscience·Christopher BishopKaren L Eskow Jaunarajs
Aug 2, 2015·Progress in Neuro-psychopharmacology & Biological Psychiatry·Colin Davidson, Fabrizio Schifano
Mar 31, 2015·Progress in Neuro-psychopharmacology & Biological Psychiatry·Leah R Mursaleen, Jonathan A Stamford
Mar 27, 2015·Parkinson's Disease·Philippe HuotJonathan M Brotchie
May 18, 2016·The Journal of Pharmacology and Experimental Therapeutics·Philippe HuotJonathan M Brotchie
Dec 17, 2017·Journal of Neural Transmission·Adjia HamadjidaPhilippe Huot
Jul 23, 2015·Therapeutic Advances in Psychopharmacology·Rachel Patel, Daniel Titheradge
Jan 7, 2018·Journal of Neural Transmission·Kathryn Lanza, Christopher Bishop
Mar 11, 2018·The Journal of Pharmacology and Experimental Therapeutics·Nicolas VeyresPhilippe Huot
May 6, 2020·Expert Opinion on Emerging Drugs·Sohaila AlShimemeriNaomi P Visanji
Aug 9, 2018·Naunyn-Schmiedeberg's Archives of Pharmacology·Adjia HamadjidaPhilippe Huot
Feb 1, 2020·Current Pharmaceutical Design·Bhumika KumarP K Sahoo
Apr 8, 2021·Journal of Experimental Pharmacology·Thomas Müller

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