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

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.