, Department of Pharmacology & Toxicology, Medicine and Psychiatry, University of Toronto, Toronto, ON, M5S 4K2, Canada; DL Global Partners Inc., 78 Baby Point Crescent, Toronto, ON, M6S 2C1, Canada. Electronic address: e.sellers@dlglobalpartners.com.
2 papers in the library · 27 citations · publishing 2002-2021
The ibogaine analog 18-methoxycoronaridine (18-MC) is metabolized primarily into 18-hydroxycoronaridine (18-HC) in human liver microsomes. This conversion is mainly catalyzed by the polymorphic enzyme CYP2C19, with a Michaelis constant (K_m) of 1.34 μM and maximum velocity (V_max) of 0.21 nmol/mg/min. Selective inhibition of CYP2C19 reduced 18-HC formation by 65%, and antibodies against CYP2C enzymes inhibited it by 70%. Other cytochrome P450 enzymes showed negligible involvement. The correlation between 18-MC metabolism and S-mephenytoin 4'-hydroxylase activity across five human liver samples further supports CYP2C19's primary role. These results suggest 18-MC could serve as a probe for CYP2C19 activity.
Nicotine dependence, primarily from smoking and vaping, is a leading cause of preventable death, and current pharmacotherapies—nicotine replacement, bupropion, and varenicline—have limited efficacy. This chapter reviews serotonin-targeted approaches, including selective serotonin reuptake inhibitors (SSRIs), 5-HT2A receptor agonists like psilocybin, 5-HT2C receptor agonists such as lorcaserin, and 5-HT2A receptor antagonists like pimavanserin. Psilocybin shows the most promise for smoking abstinence, but findings are preliminary and face approval challenges. Preclinical tests indicate distinct profiles for these drugs, and emerging biomarkers may enable personalized smoking cessation treatment.