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

Research output: Contribution to journalArticle

Original languageEnglish
Pages (from-to)15840-15849
Number of pages10
JournalJournal of the American Chemical Society
Volume141
Issue number40
Early online date13 Sep 2019
DOIs
DateAccepted/In press - 20 Aug 2019
DateE-pub ahead of print - 13 Sep 2019
DatePublished (current) - 9 Oct 2019

Abstract

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

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    Rights statement: This is the author accepted manuscript (AAM). The final published version (version of record) is available online via American Chemical Society at https://pubs.acs.org/doi/10.1021/jacs.9b06580 . Please refer to any applicable terms of use of the publisher.

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