Synthesis and Discovery of Arylpiperidinylquinazolines: New Inhibitors of the Vesicular Monoamine Transporter

Brian A. Provencher, Amy J. Eshleman, Robert A. Johnson, Xiao Shi, Olga Kryatova, Jared Nelson, Jianhua Tian, Mario Gonzalez, Peter C. Meltzer, Aaron Janowsky

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


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 vesicles and may be useful tools for characterizing drug-induced effects on human VMAT2 expression and function.

Original languageEnglish (US)
Pages (from-to)9121-9131
Number of pages11
JournalJournal of Medicinal Chemistry
Issue number20
StatePublished - Oct 25 2018

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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