Synthesis of α3β4 Nicotinic Acetylcholine Receptor Modulators Derived from Aristoquinoline That Reduce Reinstatement of Cocaine-Seeking Behavior

Growing evidence suggests that inhibition
of the α3β4
nicotinic acetylcholine receptor (nAChR) represents a promising therapeutic
strategy to treat cocaine use disorder. Recently, aristoquinoline
(1), an alkaloid from Aristotelia chilensis, was identified as an α3β4-selective nAChR inhibitor.
Here, we prepared 22 derivatives of 1 and evaluated their
ability to inhibit the α3β4 nAChR. These studies revealed
structure–activity trends and several compounds with increased
potency compared to 1 with few off-target liabilities.
Additional mechanistic studies indicated that these compounds inhibit
the α3β4 nAChR noncompetitively, but do not act as channel
blockers, suggesting they are negative allosteric modulators. Finally,
using a cocaine-primed reinstatement paradigm, we demonstrated that 1 significantly attenuates drug-seeking behavior in an animal
model of cocaine relapse. The results from these studies further support
a role for the α3β4 nAChR in the addictive properties
of cocaine and highlight the possible utility of aristoquinoline derivatives
in treating cocaine use disorder.