# Mesdopetam

Mesdopetam (INNTooltip International Nonproprietary Name; developmental code names IRL-790, IPN60170) is a dopamine D$_2$ and D$_3$ receptor antagonist with preference for the D$_3$ receptor which is under development for the treatment of Parkinson's disease, drug-induced dyskinesia, and psychotic disorders. It has been described by its developers as having "psychomotor stabilizing" properties.

## Pharmacology

The described intention behind mesdopetam was to develop a novel dopamine D$_2$ and D$_3$ receptor antagonist based on agonist- rather than antagonist-like structural motifs and with agonist-like physicochemical properties (e.g., smaller molecular size, greater hydrophilicity). It was hypothesized that this would result in an antagonist with specific dopamine receptor interactions more similar to those of agonists like dopamine but without any intrinsic activity, in turn resulting in different in vivo effects than conventional dopamine receptor antagonists. Specifically, antidyskinetic and antipsychotic effects with fewer or no motor side effects was sought. There is also extensive preclinical research to suggest that D$_3$ receptor antagonists reduce levodopa-induced dyskinesia without compromising the antiparkinsonian effects of levodopa.
Mesdopetam has 6- to 8-fold preference for the dopamine D$_3$ receptor (K$_i$ = 90 nM) over the dopamine D$_2$ receptor (K$_i$ = 540–750 nM). It displays a paradoxical agonist-like binding mode in spite of its lack of activational efficacy. By antagonizing D$_3$ autoreceptors, D$_3$ receptor antagonists like mesdopetam have been found to disinhibit dopamine release in the prefrontal cortex, ventral tegmental area, and striatum, which might be involved in the possible therapeutic benefits of these agents. The drug is also a ligand of the sigma σ$_1$ receptor (K$_i$ = 870 nM) and has some affinity for certain serotonin receptors including the serotonin 5-HT$_{1A}$ and 5-HT$_{2A}$ receptors. In animals, mesdopetam has no effect on spontaneous locomotor activity at assessed doses but antagonizes levodopa-induced dyskinesia and reduces dextroamphetamine- and dizocilpine-induced locomotor hyperactivity.

## Side effects

Side effects of mesdopetam in clinical trials have been reported to include worsened parkinsonism, headache, fatigue, asthenia, and dissociation.

## Clinical development

Mesdopetam was first described in the literature in 2012. As of September 2024, it is in phase 2/3 clinical trials for Parkinson's disease, phase 1 trials for drug-induced dyskinesia, and is in preclinical development for psychotic disorders (specifically Parkinson's disease psychosis). It is also of interest for potential treatment of impulse control disorders. In 2019, mesdopetam received an INNTooltip International Nonproprietary Name with a novel -"dopetam" suffix supposedly representing a new mechanism of action among dopamine receptor modulators. In 2023, it was reported that mesdopetam failed to meet a primary anti-dyskinetic endpoint in a phase 2b trial. However, indications of efficacy were still seen and a phase 3 trial is being planned. No dopamine D$_3$ receptor antagonists have yet completed development or been approved for the treatment of levodopa-induced dyskinesia.