6-Methylnicotine is a strong agonist at α4β2 and α3β4 nicotinic cholinergic receptors
(-)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 4{beta}2 and 3{beta}4 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 4{beta}2 and 3{beta}4 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 4{beta}2 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 4{beta}2 and 3{beta}4 nAChRs, and it also upregulates nAChRs in brain.