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

• Published in: Journal of medicinal chemistry Vol. 67; no. 1; pp. 529 - 542
• Main Authors: Rusali, Lisa E., Lopez-Hernandez, Ana M., Kremiller, Kyle M., Kulkarni, Gauri C., Gour, Abhishek, Straub, Carolyn J., Argade, Malaika D., Peters, Christian J., Sharma, Abhisheak, Toll, Lawrence, Cippitelli, Andrea, Riley, Andrew P.
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 11.01.2024; Amer Chemical Soc
• Subjects: Alkaloids - pharmacology; Alkaloids - therapeutic use; Animals; Chemistry, Medicinal; Cocaine; Drug-Seeking Behavior; Life Sciences & Biomedicine; Nicotinic Antagonists - pharmacology; Nicotinic Antagonists - therapeutic use; Pharmacology & Pharmacy; Quinolines; Receptors, Nicotinic; Science & Technology; METHAMPHETAMINE; 18-METHOXYCORONARIDINE; IBOGA ALKALOID CONGENER; LIGANDS; MORPHINE; ANXIETY; INTERPEDUNCULAR NUCLEUS; CHANNELS; BINDING; ADDICTION
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/acs.jmedchem.3c01758

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.