Synthesis and Discovery of Arylpiperidinylquinazolines: New Inhibitors of the Vesicular Monoamine Transporter
Autor: | Brian A. Provencher, Aaron Janowsky, Jared K. Nelson, Jianhua Tian, Amy J. Eshleman, Mario D. Gonzalez, Peter C. Meltzer, Robert A. Johnson, Olga Kryatova, Xiao Shi |
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Rok vydání: | 2018 |
Předmět: |
0301 basic medicine
Chemistry Techniques Synthetic Vesicular monoamine transporter 2 Ligands 03 medical and health sciences Mice 0302 clinical medicine Dopamine Drug Discovery medicine Animals Humans Binding site biology Chemistry Methamphetamine Reserpine Vesicular monoamine transporter 030104 developmental biology Monoamine neurotransmitter HEK293 Cells Biochemistry Drug Design Vesicular Monoamine Transport Proteins biology.protein Quinazolines Molecular Medicine Serotonin 030217 neurology & neurosurgery medicine.drug |
Zdroj: | Journal of medicinal chemistry. 61(20) |
ISSN: | 1520-4804 |
Popis: | Methamphetamine, a human vesicular monoamine transporter 2 (VMAT2) substrate, releases dopamine, serotonin, and norepinephrine from vesicles into the cytosol of presynaptic neurons and induces reverse transport by the monoamine transporters to increase extracellular neurotransmitters. Currently available radioligands for VMAT2 have considerable liabilities: The binding of [3H]dihydrotetrabenazine ([3H]DHTB) to a site on VMAT2 is not dependent on ATP, and [3H]reserpine binds almost irreversibly to VMAT2. Herein we demonstrate that several arylpiperidinylquinazolines (APQs) are potent inhibitors of [3H]reserpine binding at recombinant human VMAT2 expressed in HEK-293 cells. These compounds are biodiastereoselective and bioenantioselective. The lead radiolabeled APQ is unique because it binds reversibly to VMAT2 but does not bind the [3H]DHTB binding site. Furthermore, experimentation shows that several novel APQ ligands have high potency for inhibition of uptake by both HEK-VMAT2 cells and mouse striatal ve... |
Databáze: | OpenAIRE |
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