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

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.