3,4-Dihydroxyphenylalanine (
L-DOPA) treatment of
Parkinson's disease (PD) is compromised by motor side effects, such as
dyskinesia and non-motor problems, including
psychosis. Because of the marked reduction in brain
dopamine in PD and the resultant
dopamine D2 receptor supersensitivity, it is impossible to use standard potent
dopamine D2 receptor antagonists such as
haloperidol to alleviate side effects without compromising the anti-parkinsonian benefits of
L-DOPA.
Haloperidol antagonizes D2 receptors with high affinity and slowly dissociates from D2 receptors (50% dissociation at 38min). We hypothesized that a rapidly dissociating D2 antagonist might allow some functional dopaminergic transmission and thus have a profile, with respect to reduction of
dyskinesia and anti-parkinsonian effects, that was more useful therapeutically. The present study tested the principle of using a fast-off-D2
drug,
CLR151 (50% dissociation at 23s) to modify
L-DOPA actions in cynomolgus macaques with
MPTP-
parkinsonism.
CLR151 (100mg/kg p.o.) reduced
L-DOPA-induced
dyskinesia and activity in the parkinsonian macaque by 86% and 52% respectively during peak action.
CLR151 (100mg/kg) also reduced
psychosis-like behaviour (i.e. reduced apparent
visual hallucinations by 78%). Nevertheless, this dose of
CLR151 significantly reduced the duration of anti-parkinsonian action of
L-DOPA, ON-time (by 90%), and increased parkinsonian disability (by 57%). These data suggest that fast-off-D2
dopamine receptor antagonists, with D2-off-rate values close to those for
CLR151, are unlikely to be useful in the treatment of
dyskinesia and
psychosis in PD. However, fast-off-D2 drugs could provide benefit if new congeners would have an even faster dissociation rate. Such drugs are now becoming available.