6-Methylnicotine is a strong agonist at α4β2 and α3β4 nicotinic cholinergic receptors

(-)6-Methylnicotine, a chemical analogue of nicotine, has gained attention for its use in e-cigarettes and nicotine oral pouches. While the receptor subtype selectivity and potency of this compound to activate and desensitize nicotinic cholinergic receptors (nAChRs) remains unclear, it is known that chronic administration of (-)6-Methylnicotine (6-MN) potentially increases these receptors in the brain, similar to nicotine.

This study compared the effects of 6-MN and nicotine on the 4{beta}2 and 3{beta}4 nAChRs, two major nAChR subtypes involved in crucial brain functions and autonomic nervous system activities. The researchers quantitatively evaluated the receptor binding affinity and functional potency of both substances to activate and desensitize the 4{beta}2 and 3{beta}4 nAChRs. The findings revealed that 6-MN exhibits a higher level of agonism compared to nicotine for both receptor subtypes.

Furthermore, since chronic nicotine usage is known to upregulate the number of 4{beta}2 nAChRs in rat, mouse, and human brains, the researchers sought to determine if 6-MN also induces this upregulation. The results of this investigation affirm that 6-MN indeed increases the number of 4{beta}2 nAChRs in brain tissue.