Investigational drugs in Phase I and Phase II for Levodopa-induced dyskinesias

ABSTRACT

Introduction: Prolonged treatment of Parkinson’s disease (PD) with levodopa (L-DOPA) results in motor complications, including motor fluctuations and involuntary movements known as L-DOPA induced dyskinesias (LIDs). LIDs represent an additional cause of disability for PD patients and a major challenge for the clinical neurologist. Preclinical research has provided invaluable insights into the molecular and neural substrates of LIDs, identifying a number of potential targets for new anti-dyskinetic strategies.

Areas covered: This review article is centered on drugs currently in Phase I and II clinical trials for LIDs and their relative pharmacological targets, which include glutamate, acetylcholine, serotonin, adrenergic receptors and additional targets of potential therapeutic interest.

Expert opinion: LIDs are sustained by complex molecular and neurobiological mechanisms that are difficult to disentangle or target, unless one or more prevalent mechanisms are identified. In this context, the role of the serotonergic system and mGluR5 glutamate receptors seem to stand out. Interesting results have been obtained, for example, with partial 5-HT1A/5-HT1B receptor agonist eltoprazine and mGluR5 negative allosteric modulator dipraglurant. Confirmation of these results through large-scale, Phase III clinical trials will be needed, to obtain new pharmacological tools that may be used to optimize the treatment of PD patients with motor complications.

KEYWORDS:

• Acetylcholine
• adrenaline
• dyskinesia
• glutamate
• L-DOPA
• Parkinson’s disease
• serotonin

Article highlights

1. PD therapy is still based on substitutive treatment with L-DOPA, the precursor of deficient transmitter dopamine.

2. Long-term treatment with L-DOPA is hampered by the onset of involuntary movements, known as L-DOPA induced dyskinesias (LIDs), resulting from a combination of presynaptic and postsynaptic modifications occurring at the striatal level.

3. LIDs represent a disabling side effect of L-DOPA, extremely difficult to control. Various compounds targeting different elements of LID mechanism are currently being tested in Phase I and II clinical trials.

4. Phase II clinical trials have shown potential anti-dyskinetic efficacy for drugs acting on serotonergic and metabotropic glutamate receptors.

5. Confirmation of selected results from Phase II studies through large-scale, Phase III clinical trials will be needed.

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Declaration of interest

FB has a role as scientific advisor for NeuroDerm.

Additional information

Funding

This paper was not funded.