Year: 2026
Type: preprint
Abstract: (-)6-Methylnicotine (6-MN), is a structural analog of (-)nicotine that has been added to some e-cigarette/vape solutions and to nicotine oral pouches. 6-MN binds with high affinity to nicotinic cholinergic receptors (nAChRs) in brain, but its receptor subtype selectivity and its potency to activate and desensitize these receptors is unknown. Also unknown is whether chronic administration of 6-MN increases (upregulates) nAChRs in brain as does nicotine. Currently, 6-MN is unregulated in the U.S. by the FDA. Here we compared 6-MN and nicotine at α4β2 and α3β4 nAChRs, which are two major nAChR subtypes that mediate important functions in the brain and autonomic nervous system. Specifically, we quantitatively compared (-)6-MN and (-)nicotine with respect to receptor binding affinity and functional potency to activate α4β2 and α3β4 nAChRs, as well as its potency to desensitize these receptors, which is one of the key effects of nicotine. In addition, because chronic administration of nicotine upregulates the number of α4β2 nAChRs in rat, mouse and human brain, we measured whether 6-MN also increases these receptors. Our results indicate that 6-MN is a more potent agonist than nicotine at both the α4β2 and α3β4 nAChRs, and it also upregulates nAChRs in brain.
Language: English
Subfield: Molecular Biology
Domain: Life Sciences
Open Access status: green
Funder: Georgetown University
OpenAlex ID: W7222465501