posted on 2023-12-28, 03:03authored byLisa E. Rusali, Ana M. Lopez-Hernandez, Kyle M. Kremiller, Gauri C. Kulkarni, Abhishek Gour, Carolyn J. Straub, Malaika D. Argade, Christian J. Peters, Abhisheak Sharma, Lawrence Toll, Andrea Cippitelli, Andrew P. Riley
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.