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

Growing evidence suggests that inhibition of α3β4 nicotinic acetylcholine receptors (nAChRs) represents a promising therapeutic strategy to treat cocaine use disorder. Recently, aristoquinoline (1), a quinoline-containing alkaloid from Aristotelia chilensis, was identified as an α3β4-selective nAChR inhibitor. Here, we prepared a collection of derivatives of 1 and evaluated their ability to inhibit the α3β4 nAChRs. These studies revealed structure-activity trends that led to the identification of several compounds with increased potency at the α3β4 nAChR and few off-target liabilities. Additional mechanistic studies indicated that these compounds inhibit α3β4 nAChRs in a non-competitive manner but do not act as channel blockers, suggesting they are negative allosteric modulators of the α3β4 nAChR. 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 α3β4 nAChR in the addictive properties of cocaine and highlight the possible utility of aristoquinoline derivatives in treating cocaine use disorder.