The Nicotine–Tryptophan Dimer: Probing the Principal Interaction of Nicotine with the Nicotinic Acetylcholine Receptor (nAChR), the Binding Pocket in the Human Brain

To elucidate the principal interaction of nicotine (NIC) with the binding pocket of nicotinic acetylcholine receptor (nAChR), a simplified model complex comprising of N′-methyl-indolyl-2-propanamide (MIPA) and NIC was studied using infrared spectroscopy and theoretical calculations. MIPA serves as a surrogate for the tryptophan 156 residue of the α-subunit of nAChR, which was previously identified to stabilize NIC binding in a model binding pocket. The MIPA–NIC interaction stabilizes the bioactive N-methylpyrrolidinium protomer of NIC (Pyrro-H⁺, 60% population) that stimulates nAChR over the inactive pyridinium protomer (Pyri-H⁺, 40% population) via the interaction of Trp with the indole side chain of MIPA. The observed selectivity of NIC’s pyrrolidine protonation site in its complex with MIPA originates from its stabilization via cooperative interactions between the amide and indole functional groups. This work illustrates the importance of fundamental interactions at the molecular level in describing biological activity between an agonist and the binding pocket of the nAChR.