The Novel CYP2A6 Inhibitor, DLCI-1, Decreases Nicotine Self-Administration in Mice

• Published in: The Journal of pharmacology and experimental therapeutics 2020-01, Vol.372 (1), p.21-29
• Main Authors: Chen, Yen-Chu, Fowler, James P., Wang, Jing, Watson, Christy J.W., Sherafat, Yasmine, Staben, Andres, Lazarus, Philip, Denton, Travis T., Fowler, Christie D.
• Format: Article
• Language: English
• Subjects: Animals; Behavioral Pharmacology; Cytochrome P-450 CYP2A6 - antagonists & inhibitors; Cytochrome P-450 CYP2A6 - metabolism; Enzyme Inhibitors - administration & dosage; Enzyme Inhibitors - adverse effects; Enzyme Inhibitors - pharmacology; Enzyme Inhibitors - therapeutic use; Female; Liver - drug effects; Liver - metabolism; Male; Mice; Mice, Inbred C57BL; Nicotine - metabolism; Smoking Cessation Agents - administration & dosage; Smoking Cessation Agents - adverse effects; Smoking Cessation Agents - pharmacology; Smoking Cessation Agents - therapeutic use; Thiophenes - administration & dosage; Thiophenes - adverse effects; Thiophenes - pharmacology; Thiophenes - therapeutic use; Tobacco Use Disorder - drug therapy
• ISSN: 0022-3565; 1521-0103
• DOI: 10.1124/jpet.119.260653

During tobacco and e-cigarette use, nicotine is mainly metabolized in the human liver by cytochrome P450 2A6 (CYP2A6). Given that a slower CYP2A6 metabolism has been associated with less vulnerability to develop nicotine dependence, the current studies sought to validate a novel CYP2A6 inhibitor, (5-(4-ethylpyridin-3-yl)thiophen-2-yl)methanamine (DLCI-1), for its effects on intravenous nicotine self-administration. Male and female mice were trained to self-administer nicotine across daily sessions. Once stable responding was achieved, DLCI-1 or vehicle control was administered prior to nicotine sessions. We found that the lower 25 mg/kg and moderate 50 mg/kg doses of DLCI-1 induced a significant decrease in nicotine intake for both males and females. DLCI-1 was further shown to be more effective than a moderate 1 mg/kg dose of bupropion on reducing nicotine intake and did not exert the adverse behavioral effects found with a high 75 mg/kg dose of bupropion. Although mice treated with DLCI-1 self-administered significantly less nicotine, similar nicotine-mediated behavioral effects on locomotion were observed. Together, along with the analysis of nicotine metabolites during self-administration, these findings support the contention that blocking hepatic nicotine metabolism would allow for similar activation of nicotinic acetylcholine receptors at lower nicotine doses. Moreover, these effects of DLCI-1 were specific to nicotine self-administration, as DLCI-1 did not result in any behavioral changes during food self-administration. Taken together, these studies validate DLCI-1 as a novel compound to decrease nicotine consumption, which may thereby promote tobacco and nicotine product cessation. Current pharmacological approaches for nicotine and tobacco cessation have only been able to achieve limited efficaciousness in promoting long-term abstinence. In this work, we characterize the effects of a novel compound, (5-(4-ethylpyridin-3-yl)thiophen-2-yl)methanamine (DLCI-1), which inhibits the main enzyme that metabolizes nicotine, and we report a significant decrease in intravenous nicotine self-administration in male and female mice, supporting the potential of DLCI-1 as a novel tobacco cessation pharmacotherapeutic.