Identification and synthesis of novel alkaloids from the root system of Nicotiana tabacum : Affinity for neuronal nicotinic acetylcholine receptors

Abstract A novel pyridine derivative, 3,5- bis -(1-methyl-pyrrolidin-2-yl)-pyridine, and a pair of diastereomers of 1,1′-dimethyl-[2,3′]bipyrrolidinyl were isolated from the root of Nicotiana tabacum plants and identified as novel alkaloids by GC-MS analysis. The structures of these new alkaloids were confirmed by total synthesis. The affinities of these novel alkaloids, and other structurally related compounds for α4β2*, α7* neuronal nicotinic acetylcholine receptors (nAChRs), and for nAChRs mediating nicotine-evoked dopamine release from rat striatum were also assessed. The results indicate that these compounds do not interact with α7* nAChRs, but inhibit [ 3 H]nicotine binding to the α4β2* nAChR subtype. The results also demonstrate that these compounds act as antagonists at nAChRs mediating nicotine-evoked dopamine release from rat striatum.