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.