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A novel MDMA analogue, UWA-101, that lacks psychoactivity and cytotoxicity, enhances L-DOPA benefit in parkinsonian primates.
FASEB J 2012; 26(5):2154-63FJ

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+Show Affiliations

Toronto Western Research Institute, 399 Bathurst St, MC-11-419, Toronto, ON, Canada.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

22345403

Citation

Johnston, Tom H., et al. "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, vol. 26, no. 5, 2012, pp. 2154-63.
Johnston TH, Millar Z, Huot P, et al. A novel MDMA analogue, UWA-101, that lacks psychoactivity and cytotoxicity, enhances L-DOPA benefit in parkinsonian primates. FASEB J. 2012;26(5):2154-63.
Johnston, T. H., Millar, Z., Huot, P., Wagg, K., Thiele, S., Salomonczyk, D., ... Brotchie, J. M. (2012). 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, 26(5), pp. 2154-63. doi:10.1096/fj.11-195016.
Johnston TH, et al. A Novel MDMA Analogue, UWA-101, That Lacks Psychoactivity and Cytotoxicity, Enhances L-DOPA Benefit in Parkinsonian Primates. FASEB J. 2012;26(5):2154-63. PubMed PMID: 22345403.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - A novel MDMA analogue, UWA-101, that lacks psychoactivity and cytotoxicity, enhances L-DOPA benefit in parkinsonian primates. AU - Johnston,Tom H, AU - Millar,Zak, AU - Huot,Philippe, AU - Wagg,Keith, AU - Thiele,Sherri, AU - Salomonczyk,Danielle, AU - Yong-Kee,Christopher J, AU - Gandy,Michael N, AU - McIldowie,Matthew, AU - Lewis,Katie D, AU - Gomez-Ramirez,Jordi, AU - Lee,Joohyung, AU - Fox,Susan H, AU - Martin-Iverson,Mathew, AU - Nash,Joanne E, AU - Piggott,Matthew J, AU - Brotchie,Jonathan M, Y1 - 2012/02/17/ PY - 2012/2/21/entrez PY - 2012/2/22/pubmed PY - 2012/6/30/medline SP - 2154 EP - 63 JF - FASEB journal : official publication of the Federation of American Societies for Experimental Biology JO - FASEB J. VL - 26 IS - 5 N2 - 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. SN - 1530-6860 UR - https://www.unboundmedicine.com/medline/citation/22345403/A_novel_MDMA_analogue_UWA_101_that_lacks_psychoactivity_and_cytotoxicity_enhances_L_DOPA_benefit_in_parkinsonian_primates_ L2 - http://www.fasebj.org/doi/full/10.1096/fj.11-195016?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -