Probing Binding Interactions of Cytisine Derivatives to the α4β2 Nicotinic Acetylcholine Receptor

• DOI: 10.1021/jacs.9b06580
• Publication Date: 2019-09-13T22:22:22Z
• Authors: Annet E.M. Blom; Hugo Rego Campello; Henry A. Lester; Timothy Gallagher; Dennis A. Dougherty
• Keywords: Cytisine

Nicotinic acetylcholine receptors (nAChRs) are crucial for communication between synapses in the central nervous system. As such, they also implicated several neuropsychiatric and addictive diseases. Cytisine is a partial agonist of some nAChRs has been used smoking cessation. Previous studies have established binding model agonists to nAChR subtypes. Here, we evaluate extent which this applies cytisine at α4β2 nAChR, subtype that known play prominent role nicotine addiction. Along with commonly seen cation−π interaction two hydrogen bonds, find makes second site. We evaluated series C(10)-substituted derivatives, using two-electrode voltage-clamp electrophysiology noncanonical amino acid mutagenesis. Double-mutant cycle analyses revealed C(10) substitution generally strengthens newly interaction, while it weakens bond typically LeuE complementary subunit. The results suggest how derivatives substituted (as well as C(9)/C(10)) adjust their orientation, response pyridone ring substitution.