UWA-101 (also known as α-cyclopropyl-MDMA) is a

phenethylamine Phenethylamine (PEA) is an organic compound, natural monoamine alkaloid, and trace amine, which acts as a central nervous system stimulant in humans. In the brain, phenethylamine regulates monoamine neurotransmission by binding to trace ami ...

derivative researched as a potential treatment for

Parkinson's disease Parkinson's disease (PD), or simply Parkinson's, is a neurodegenerative disease primarily of the central nervous system, affecting both motor system, motor and non-motor systems. Symptoms typically develop gradually and non-motor issues become ...

. Its chemical structure is very similar to that of the illegal drug

MDMA 3,4-Methylenedioxymethamphetamine (MDMA), commonly known as ecstasy (tablet form), and molly (crystal form), is an empathogen–entactogenic drug with stimulant and minor Psychedelic drug, psychedelic properties. In studies, it has been used ...

, the only difference being the replacement of the α-

methyl In organic chemistry, a methyl group is an alkyl derived from methane, containing one carbon atom bonded to three hydrogen atoms, having chemical formula (whereas normal methane has the formula ). In formulas, the group is often abbreviated as ...

group with an α-

cyclopropyl A cyclopropyl group is a chemical structure derived from cyclopropane; it is typically produced in a cyclopropanation reaction. The group has an empirical formula of C3H5 and chemical bonds from each of the three carbons to both of the other tw ...

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. However the illegal status of MDMA and concerns about its potential for recreational use,

neurotoxicity Neurotoxicity is a form of toxicity in which a biological, chemical, or physical agent produces an adverse effect on the structure or function of the central and/or peripheral nervous system. It occurs when exposure to a substance – specifical ...

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. Replacing the α-methyl with a cyclopropyl dramatically reduces affinity for the noradrenaline transporter and 5-HT_2A receptor, while retaining high

serotonin transporter The serotonin transporter (SERT or 5-HTT) also known as the sodium-dependent serotonin transporter and solute carrier family 6 member 4 is a protein that in humans is encoded by the SLC6A4 gene. SERT is a type of monoamine transporter protein t ...

affinity and markedly increasing affinity for the

dopamine transporter The dopamine transporter (DAT, also sodium-dependent dopamine transporter) is a membrane-spanning protein coded for in humans by the ''SLC6A3'' gene (also known as ''DAT1''), that pumps the neurotransmitter dopamine out of the synaptic cleft ba ...

(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 Burkitt's lymphoma is a cancer of the lymphatic system, particularly B lymphocytes found in the germinal center. It is named after Denis Parsons Burkitt, the Irish surgeon who first described the disease in 1958 while working in equatorial Africa ...

cells ''in vitro''. UWA-121 is the (''R'')-

enantiomer In chemistry, an enantiomer (Help:IPA/English, /ɪˈnænti.əmər, ɛ-, -oʊ-/ Help:Pronunciation respelling key, ''ih-NAN-tee-ə-mər''), also known as an optical isomer, antipode, or optical antipode, is one of a pair of molecular entities whi ...

of UWA-101 and the (''S'')-enantiomer is UWA-122. Both are active monoamine reuptake inhibitors. UWA-121 is an SDRI with 10-fold preference for inhibition of dopamine reuptake over serotonin reuptake while UWA-122 is a highly selective

serotonin reuptake inhibitor A serotonin reuptake inhibitor (SRI) is a type of drug which acts as a reuptake inhibitor of the neurotransmitter serotonin (5-hydroxytryptamine, or 5-HT) by blocking the drug action, action of the serotonin transporter (SERT). This in turn lea ...

. Another relative is UWA-104 ("α-isopropyl-MDMA"), which is also active. It is a selective

dopamine reuptake inhibitor A dopamine reuptake inhibitor (DRI) is a class of drug which acts as a reuptake inhibitor of the monoamine neurotransmitter dopamine by blocking the action of the dopamine transporter (DAT). Reuptake inhibition is achieved when extracellular dop ...

, with greater than 30-fold selectivity over the other

monoamine transporter Monoamine transporters (MATs) are proteins that function as integral Cell membrane, plasma-membrane Neurotransmitter transporter, transporters to regulate concentrations of extracellular monoamine neurotransmitters. The three major classes are se ...

s or the serotonin 5-HT_2A receptor. Other analogues include UWA-091 ("α-propyl-MDMA"), UWA-102 ("α-''tert''-butyl-MDMA"), and UWA-001 ("α-phenyl-MDMA"). The ''in vitro'' pharmacological activities of UWA-101, UWA-104, and UWA-001 have been reported.

References

External links

Do neurologists dance? A personal experience of Parkinson's disease & MDMA
Tim Lawrence, 2003 {{Phenethylamines Methylenedioxyphenethylamines Serotonin–dopamine reuptake inhibitors Substituted amphetamines

See also

References

External links