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J Med Chem ; 67(1): 529-542, 2024 01 11.
Article in English | MEDLINE | ID: mdl-38151460

ABSTRACT

Growing evidence suggests that inhibition of the α3ß4 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 α3ß4-selective nAChR inhibitor. Here, we prepared 22 derivatives of 1 and evaluated their ability to inhibit the α3ß4 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 α3ß4 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 α3ß4 nAChR in the addictive properties of cocaine and highlight the possible utility of aristoquinoline derivatives in treating cocaine use disorder.


Subject(s)
Alkaloids , Cocaine , Quinolines , Receptors, Nicotinic , Animals , Alkaloids/pharmacology , Alkaloids/therapeutic use , Drug-Seeking Behavior , Nicotinic Antagonists/pharmacology , Nicotinic Antagonists/therapeutic use
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