A novel MDMA analogue, UWA‐101, that lacks psychoactivity and cytotoxicity, enhances <scp>l</scp> ‐DOPA benefit in parkinsonian primates
Bibliographic record
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.—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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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".