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

15 November 2023, Version 2


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 non-competitively, 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.


Nicotinic Acetylcholine Receptor
Structure-Activity Relationships
Drug Addiction

Supplementary materials

Supporting Information
Supporting Information includes: Supplementary Tables S1-3, Figures S1-2, Reverse Phase HPLC chromatograms, and NMR Spectra (1H and 13C)


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