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

T.H. Johnston, Zak Millar, P. Huot, K. Wagg, S. Thiele, D. Salomonczyk, C.J. Yong-Kee, Michael Gandy, M. Mcildowie, Katie Lewis, J. Gomez-Ramirez, J. Lee, S.H. Fox, Mathew Martin-Iverson, J.E. Nash, Matthew Piggott, J.M. Brotchie

Research output: Contribution to journalArticle

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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 alpha-substituted MDMA analogues, one of which, bearing an alpha-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.-Johnston, T. H., Millar, Z., Huot, P., Wagg, K., Thiele, S., Salomonczyk, D., Yong-Kee, C. J., Gandy, M. N., McIldowie, M., Lewis, K. D., Gomez-Ramirez, J., Lee, J., Fox, S. H., Martin-Iverson, M., Nash, J. E., Piggott, M. J., Brotchie, J. M. A novel MDMA analogue, UWA-101, that lacks psychoactivity and cytotoxicity, enhances L-DOPA benefit in parkinsonian primates. FASEB J. 26, 2154-2163 (2012). www.fasebj.org
Original languageEnglish
Pages (from-to)2154-2163
JournalFASEB Journal
Volume26
DOIs
Publication statusPublished - 2012

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N-Methyl-3,4-methylenedioxyamphetamine
Cytotoxicity
Primates
Parkinson Disease
Street Drugs
Assays
Animals
Bearings (structural)
Animal Models
Antiparkinson Agents
Receptor, Serotonin, 5-HT2A
Dopamine Agents
N-methyl-1-cyclopropyl-1-piperonylmethylamine
Dyskinesias
Therapeutics
Dopamine
Serotonin
Cell Survival
Norepinephrine
Eating

Cite this

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, 26, 2154-2163. https://doi.org/10.1096/fj.11-195016
Johnston, T.H. ; Millar, Zak ; Huot, P. ; Wagg, K. ; Thiele, S. ; Salomonczyk, D. ; Yong-Kee, C.J. ; Gandy, Michael ; Mcildowie, M. ; Lewis, Katie ; Gomez-Ramirez, J. ; Lee, J. ; Fox, S.H. ; Martin-Iverson, Mathew ; Nash, J.E. ; Piggott, Matthew ; Brotchie, J.M. / A novel MDMA analogue, UWA-101, that lacks psychoactivity and cytotoxicity, enhances L-DOPA benefit in parkinsonian primates. In: FASEB Journal. 2012 ; Vol. 26. pp. 2154-2163.
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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 alpha-substituted MDMA analogues, one of which, bearing an alpha-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.-Johnston, T. H., Millar, Z., Huot, P., Wagg, K., Thiele, S., Salomonczyk, D., Yong-Kee, C. J., Gandy, M. N., McIldowie, M., Lewis, K. D., Gomez-Ramirez, J., Lee, J., Fox, S. H., Martin-Iverson, M., Nash, J. E., Piggott, M. J., Brotchie, J. M. A novel MDMA analogue, UWA-101, that lacks psychoactivity and cytotoxicity, enhances L-DOPA benefit in parkinsonian primates. FASEB J. 26, 2154-2163 (2012). www.fasebj.org",
author = "T.H. Johnston and Zak Millar and P. Huot and K. Wagg and S. Thiele and D. Salomonczyk and C.J. Yong-Kee and Michael Gandy and M. Mcildowie and Katie Lewis and J. Gomez-Ramirez and J. Lee and S.H. Fox and Mathew Martin-Iverson and J.E. Nash and Matthew Piggott and J.M. Brotchie",
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Johnston, TH, Millar, Z, Huot, P, Wagg, K, Thiele, S, Salomonczyk, D, Yong-Kee, CJ, Gandy, M, Mcildowie, M, Lewis, K, Gomez-Ramirez, J, Lee, J, Fox, SH, Martin-Iverson, M, Nash, JE, Piggott, M & Brotchie, JM 2012, 'A novel MDMA analogue, UWA-101, that lacks psychoactivity and cytotoxicity, enhances L-DOPA benefit in parkinsonian primates' FASEB Journal, vol. 26, pp. 2154-2163. https://doi.org/10.1096/fj.11-195016

A novel MDMA analogue, UWA-101, that lacks psychoactivity and cytotoxicity, enhances L-DOPA benefit in parkinsonian primates. / Johnston, T.H.; Millar, Zak; Huot, P.; Wagg, K.; Thiele, S.; Salomonczyk, D.; Yong-Kee, C.J.; Gandy, Michael; Mcildowie, M.; Lewis, Katie; Gomez-Ramirez, J.; Lee, J.; Fox, S.H.; Martin-Iverson, Mathew; Nash, J.E.; Piggott, Matthew; Brotchie, J.M.

In: FASEB Journal, Vol. 26, 2012, p. 2154-2163.

Research output: Contribution to journalArticle

TY - JOUR

T1 - A novel MDMA analogue, UWA-101, that lacks psychoactivity and cytotoxicity, enhances L-DOPA benefit in parkinsonian primates

AU - Johnston, T.H.

AU - Millar, Zak

AU - Huot, P.

AU - Wagg, K.

AU - Thiele, S.

AU - Salomonczyk, D.

AU - Yong-Kee, C.J.

AU - Gandy, Michael

AU - Mcildowie, M.

AU - Lewis, Katie

AU - Gomez-Ramirez, J.

AU - Lee, J.

AU - Fox, S.H.

AU - Martin-Iverson, Mathew

AU - Nash, J.E.

AU - Piggott, Matthew

AU - Brotchie, J.M.

PY - 2012

Y1 - 2012

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 alpha-substituted MDMA analogues, one of which, bearing an alpha-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.-Johnston, T. H., Millar, Z., Huot, P., Wagg, K., Thiele, S., Salomonczyk, D., Yong-Kee, C. J., Gandy, M. N., McIldowie, M., Lewis, K. D., Gomez-Ramirez, J., Lee, J., Fox, S. H., Martin-Iverson, M., Nash, J. E., Piggott, M. J., Brotchie, J. M. A novel MDMA analogue, UWA-101, that lacks psychoactivity and cytotoxicity, enhances L-DOPA benefit in parkinsonian primates. FASEB J. 26, 2154-2163 (2012). www.fasebj.org

AB - 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 alpha-substituted MDMA analogues, one of which, bearing an alpha-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.-Johnston, T. H., Millar, Z., Huot, P., Wagg, K., Thiele, S., Salomonczyk, D., Yong-Kee, C. J., Gandy, M. N., McIldowie, M., Lewis, K. D., Gomez-Ramirez, J., Lee, J., Fox, S. H., Martin-Iverson, M., Nash, J. E., Piggott, M. J., Brotchie, J. M. A novel MDMA analogue, UWA-101, that lacks psychoactivity and cytotoxicity, enhances L-DOPA benefit in parkinsonian primates. FASEB J. 26, 2154-2163 (2012). www.fasebj.org

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DO - 10.1096/fj.11-195016

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JO - FASEB Journal

JF - FASEB Journal

SN - 0892-6638

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