Evaluation of the Relationship between Vesicular Monoamine Transporter 2 (VMAT2) Inhibition and Neurologic Adverse Events in Approved Drugs

Vesicular monoamine transporter 2 (VMAT2) is an internal membrane protein found predominantly in the central nervous system that plays an integral role in the transport of biogenic monoamines (e.g., dopamine, serotonin, and norepinephrine) into synaptic vesicles for storage within the neuron. While multiple drugs that inhibit VMAT2 have been approved by the US Food and Drug Administration (FDA) for the treatment of hyperkinetic movement disorders, it has been reported that off-target interaction with VMAT2 may lead to neuropsychiatric consequences. In the present study an <i>in vitro</i> analysis was conducted for 257 chemically diverse compounds, most of which were FDA-approved drugs, to calculate the IC₅₀ values for inhibition of dopamine uptake at the VMAT2. The results of this study revealed that a total of 55 chemicals have strong inhibitory activities on dopamine uptake (IC₅₀ < 1 μM), some of which were not previously reported. Furthermore, 69 chemicals exhibited weak inhibitory activity on dopamine uptake between 1 and 10 μM, while 133 showed minimal to no impact on dopamine uptake (IC₅₀ > 10 μM). The IC₅₀ values and resulting inhibition categories were compared to the reported neurologic adverse events including deliria, Parkinson's-related symptoms, dyskinesia, and suicidal ideation in the FDA Adverse Event Reporting System (FAERS) and drug labeling; however, no correlation was established between adverse events and VMAT2 inhibition. Additional analysis indicated that many of the compounds that inhibited dopamine uptake at VMAT2 were frequently known to interact with serotonin, dopamine, or adrenergic receptors; therefore, it is possible that a synergistic interaction between VMAT2 and one or more additional targets may be responsible for previously reported neurological adverse events.