Dipraglurant

Dipraglurant is a selective mGlu5 negative allosteric modulator that is rapidly absorbed after oral administration, readily crosses the blood-brain barrier, and shows a strong correlation between plasma concentration and behavioural efficacy ^[1]. In rodent studies it dose-dependently reduced haloperidol-induced catalepsy, a motor readout, and produced anxiolytic-like effects in the Vogel conflict test, antidepressant-like effects in the forced swim test and reduced marble burying, a proxy for compulsive behaviour, without impairing rotarod performance or general locomotion ^[1]. This separation of behavioural benefit from motor impairment is a desirable property for a movement-disorder drug.

In the clinic, a randomized, double-blind, placebo-controlled safety study of dipraglurant in Parkinson's disease demonstrated tolerability and positive exploratory secondary outcomes of reduced levodopa-induced dyskinesia, positioning it alongside mavoglurant as an mGlu5-based anti-dyskinetic candidate ^[2]. The combination of a motor benefit with preclinical activity against anxiety, depression and compulsivity is significant because these non-motor symptoms are highly prevalent in Parkinson's disease and poorly addressed by existing dopaminergic therapy ^[1][2]. Development has focused on Parkinson's disease dyskinesia, with dystonia also explored.

Preclinical evidence with early positive clinical safety and exploratory signals

In its controlled Parkinson's disease safety study dipraglurant was well tolerated, and in preclinical models efficacy was achieved without sedation, ataxia or motor impairment on the rotarod. As a central mGlu5 modulator, class effects such as dizziness are plausible at higher exposures. Dipraglurant remains investigational and is not approved for clinical use.

Dipraglurant was developed by the Swiss company Addex Therapeutics as ADX48621 and advanced into clinical testing for levodopa-induced dyskinesia, becoming one of the notable non-Novartis entrants in the mGlu5 dyskinesia field. Preclinical characterization emphasized its favourable pharmacokinetics and broad behavioural activity. The program also explored an extended-release formulation and applications such as dystonia, reflecting continued interest in the molecule.

Dipraglurant is regarded as a credible, well-profiled mGlu5 negative allosteric modulator and is often cited together with mavoglurant when reviewing glutamatergic approaches to Parkinson's dyskinesia. Its demonstrated preclinical activity against non-motor symptoms has earned it attention as a potential dual-benefit agent. It is discussed in research and patient-advocacy circles interested in glutamatergic movement-disorder therapy rather than used recreationally or as a supplement.