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
U2 - 10.1096/fj.11-195016
DO - 10.1096/fj.11-195016
M3 - Article
C2 - 22345403
SN - 0892-6638
VL - 26
SP - 2154
EP - 2163
JO - FASEB Journal
JF - FASEB Journal
ER -