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CORESTA Meeting, Smoke Science/Product Technology, 2023, Cancun, STPOST 52 (also presented at TSRC 2023)

Chemical, pharmacological, and toxicological assessment of 6-methylnicotine

CHEETHAM A.G.(1); PLUNKETT S.E.(1,2); MARKING S.(2); CAMPBELL P.(2); COFFA B.G.(2); GILLILAND III, S.(2); McFADDEN L.(1); SCIAN M.(1)
(1) Enthalpy Specialty Labs, Richmond, VA, U.S.A.; (2) Consilium Sciences, Richmond, VA, U.S.A.

There is interest in nicotine-related alkaloids for both recreational use and pharmaceutical applications such as smoking cessation and central nervous system disorders conditions such as Parkinson’s, Tourette’s, and ADHD. Nicotine is one of many alkaloids produced by the tobacco plant (Nicotiana tabacum species) and more recently synthesized for commercial use. The compound 6 methylnicotine (CAS# 101540-79-8) has been identified as a nicotine analogue of interest based on its chemical structure, sensorial properties, and commercial availability. Chemical, pharmacological, and toxicological assessments were conducted on 6-methylnicotine and compared to pharmaceutical grade (S)-nicotine. Samples of 6-methylnicotine analysed included both freebase and salt forms, as well as in e-liquid formulations containing propylene glycol (PG) and vegetable glycerin (VG) for use in an electronic nicotine delivery system (ENDS). Chemical analysis confirmed the sample was 6 methylnicotine, racemic, and ~98 % pure utilizing 1H NMR, chiral UPLC UV, and GC-MS, respectively. The aerosol transfer efficiency of 6-methylnicotine was similar to that of nicotine (82.5 ± 2.9 % vs. 85.6 ± 0.6 % for freebase forms). The QSAR computational pharmacology of 6 methylnicotine is similar in potency and binding affinity to that of (S)-nicotine in in vivo and ex vivo models. Conventional in vitro toxicology testing (Neutral Red and Ames) demonstrated 6 methylnicotine salt e-liquid formulations have similar cellular cytotoxicity and mutagenicity to the analogous (S)-nicotine salt e-liquid formulation. The totality of available evidence indicates that 6 methylnicotine has comparable chemical, pharmacological, and toxicological properties to the more widely used nicotine.