UWA-101, also known asα-cyclopropyl-3,4-methylenedioxyphenethylamine (α-cPr-MDPEA), is aphenethylamine derivative researched as a potential treatment forParkinson's disease. Its chemical structure is very similar to that of the illegal drugMDMA, 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 thenoradrenaline transporter and5-HT2A receptor, while retaining highserotonin transporter affinity and markedly increasing affinity for thedopamine transporter (and as such, it is one of the few selective SDRIs orserotonin-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.[6] 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 againstBurkitt's lymphoma cellsin vitro.[7][8]
UWA-121 is the (R)-enantiomer of UWA-101 and the (S)-enantiomer isUWA-122.[9] Both are active monoamine reuptake inhibitors.[9] UWA-121 is an SDRI with 10-fold preference for inhibition of dopamine reuptake over serotonin reuptake while UWA-122 is a highly selectiveserotonin reuptake inhibitor.[9]
Another relative isUWA-104 ("α-isopropyl-MDMA"), which is also active.[6] It is a selectivedopamine reuptake inhibitor, with greater than 30-fold selectivity over the othermonoamine transporters or the serotonin5-HT2A receptor.[6] Other analogues includeUWA-091 ("α-propyl-MDMA"),UWA-102 ("α-tert-butyl-MDMA"), andUWA-001 ("α-phenyl-MDMA").[6] Thein vitro pharmacological activities of UWA-101, UWA-104, and UWA-001 have been reported.[6]
^abcHuot P, Johnston TH, Lewis KD, Koprich JB, Reyes MG, Fox SH, et al. (July 2014). "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.doi:10.1016/j.neuropharm.2014.01.012.PMID24447715.S2CID37160397.
