UWA-101 explained

UWA-101 (also known as α-cyclopropyl-MDMA) is a phenethylamine derivative researched as a potential treatment for Parkinson's disease. Its chemical structure is very similar to that of the illegal drug MDMA, the only difference being the replacement of the α-methyl group with an α-cyclopropyl group. MDMA has been found in animal studies and reported in unauthorised human self-experiments to be effective in the short-term relief of side-effects of Parkinson's disease therapy, most notably levodopa-induced dyskinesia.[1] [2] [3] [4] However the illegal status of MDMA and concerns about its potential for recreational use, neurotoxicity and potentially dangerous side effects mean that it is unlikely to be investigated for medical use in this application, and so alternative analogues were investigated.[5]

Replacing the α-methyl with a cyclopropyl dramatically reduces affinity for the noradrenaline transporter and 5-HT2A receptor, while retaining high serotonin transporter affinity and markedly increasing affinity for the dopamine transporter (and as such, it is one of the few selective SDRIs or serotonin-dopamine reuptake inhibitors). This change causes UWA-101 to lack cytotoxicity and MDMA-like behavioral effects in animals, while retaining similar or slightly improved antidyskinetic effectiveness when compared to MDMA. This research was a continuation of earlier work from the same team led by medicinal chemist Matthew Piggott, at the University of Western Australia, which showed that replacing the α-methyl group of MDMA with larger aromatic ring systems produced compounds which lacked psychoactivity and neurotoxicity, but had potent anti-cancer effects against Burkitt's lymphoma cells in vitro.[6] [7]

UWA-121 is the (R)-enantiomer of UWA-101 and the (S)-enantiomer is UWA-122.[8] Both are active monoamine reuptake inhibitors.

Another relative is UWA-104 ("α-isopropyl-MDMA"), which is also active.[9]

See also

External links

Notes and References

  1. Schmidt WJ, Mayerhofer A, Meyer A, Kovar KA . Ecstasy counteracts catalepsy in rats, an anti-parkinsonian effect? . Neuroscience Letters . 330 . 3 . 251–4 . September 2002 . 12270640 . 10.1016/s0304-3940(02)00823-6 . 41609012 .
  2. Iravani MM, Jackson MJ, Kuoppamäki M, Smith LA, Jenner P . 3,4-methylenedioxymethamphetamine (ecstasy) inhibits dyskinesia expression and normalizes motor activity in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-treated primates . The Journal of Neuroscience . 23 . 27 . 9107–15 . October 2003 . 14534244 . 6740822 . 10.1523/JNEUROSCI.23-27-09107.2003 .
  3. Lebsanft HB, Kohles T, Kovar KA, Schmidt WJ . 3,4-Methylenedioxymethamphetamine counteracts akinesia enantioselectively in rat rotational behavior and catalepsy . Synapse . 55 . 3 . 148–55 . March 2005 . 15602749 . 10.1002/syn.20102 . 24601744 .
  4. Huot P, Johnston TH, Lewis KD, Koprich JB, Reyes MG, Fox SH, Piggott MJ, Brotchie JM . Characterization of 3,4-methylenedioxymethamphetamine (MDMA) enantiomers in vitro and in the MPTP-lesioned primate: R-MDMA reduces severity of dyskinesia, whereas S-MDMA extends duration of ON-time . The Journal of Neuroscience . 31 . 19 . 7190–8 . May 2011 . 21562283 . 6703214 . 10.1523/JNEUROSCI.1171-11.2011 .
  5. MDMA and Parkinson's: Lots of Research, Few Practical Answers. . Ilsa . Jerome . MAPS . XVI . 1 . 16–18 . Spring 2008 . 2012-04-09 . 2011-09-15 . https://web.archive.org/web/20110915145200/http://www.maps.org/news-letters/v16n1/mdma_parkinsons.pdf . live .
  6. Gandy MN, McIldowie M, Lewis K, Wasik AM, Salomonczyk D, Wagg K, Millar ZA, Tindiglia D, Huot P, Johnston T, Thiele S . 2010 . Redesigning the designer drug ecstasy: nonpsychoactive MDMA analogues exhibiting Burkitt's lymphoma cytotoxicity . MedChemComm . 1 . 4. 287–293 . 10.1039/c0md00108b.
  7. Wasik AM, Gandy MN, McIldowie M, Holder MJ, Chamba A, Challa A, Lewis KD, Young SP, Scheel-Toellner D, Dyer MJ, Barnes NM, Piggott MJ, Gordon J . Enhancing the anti-lymphoma potential of 3,4-methylenedioxymethamphetamine ('ecstasy') through iterative chemical redesign: mechanisms and pathways to cell death . Investigational New Drugs . 30 . 4 . 1471–83 . August 2012 . 21850491 . 10.1007/s10637-011-9730-5 . 20880580 . 2019-09-18 . 2020-03-10 . https://web.archive.org/web/20200310010226/http://pure-oai.bham.ac.uk/ws/files/10275792/MDMA_Analogues_Wasik_et_al.pdf . live .
  8. Huot P, Johnston TH, Lewis KD, Koprich JB, Reyes MG, Fox SH, Piggott MJ, Brotchie JM . UWA-121, a mixed dopamine and serotonin re-uptake inhibitor, enhances L-DOPA anti-parkinsonian action without worsening dyskinesia or psychosis-like behaviours in the MPTP-lesioned common marmoset . Neuropharmacology . 82 . 76–87 . July 2014 . 24447715 . 10.1016/j.neuropharm.2014.01.012 . 37160397 .
  9. Johnston TH, Millar Z, Huot P, Wagg K, Thiele S, Salomonczyk D, Yong-Kee CJ, Gandy MN, McIldowie M, Lewis KD, Gomez-Ramirez J, Lee J, Fox SH, Martin-Iverson M, Nash JE, Piggott MJ, Brotchie JM . A novel MDMA analogue, UWA-101, that lacks psychoactivity and cytotoxicity, enhances L-DOPA benefit in parkinsonian primates . FASEB Journal . 26 . 5 . 2154–63 . May 2012 . 22345403 . 10.1096/fj.11-195016 . free . 37589231 .

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