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 in vitro 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.