| アブストラクト | 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 IC(50) 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 (IC(50) < 1 muM), some of which were not previously reported. Furthermore, 69 chemicals exhibited weak inhibitory activity on dopamine uptake between 1 and 10 muM, while 133 showed minimal to no impact on dopamine uptake (IC(50) > 10 muM). The IC(50) 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. |
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| ジャーナル名 | ACS pharmacology & translational science |
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| Pubmed追加日 | 2026/1/15 |
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| 投稿者 | Racz, Rebecca; Kozell, Laura B; Eshleman, Amy J; Bloom, Shelley H; Wolfrum, Katherine M; Schmachtenberg, Jennifer L; Swanson, Tracy L; Ngai, Jamie; Schutzer, William E; Janowsky, Aaron; Abbas, Atheir I; Stavitskaya, Lidiya |
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| 組織名 | Office of Clinical Pharmacology, Center for Drug Evaluation and Research, Food;and Drug Administration, Silver Spring, Maryland 20993, United States. RINGGOLD:;4137;Research Service, Veterans Affairs Portland Health Care System, Portland, Oregon;97239, United States.;Department of Behavioral Neuroscience, Oregon Health & Science University,;Portland, Oregon 97239, United States. RINGGOLD: 6684;Department of Psychiatry, Oregon Health & Science University, Portland, Oregon;97239, United States. RINGGOLD: 6684;University of Michigan, School of Pharmacy, Ann Arbor, Michigan 48109, United;States. |
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| Pubmed リンク | https://www.ncbi.nlm.nih.gov/pubmed/41536287/ |
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