Probing Binding Interactions of Cytisine Derivatives to the α4β2 Nicotinic Acetylcholine Receptor.
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| 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-π interaction and two hydrogen bonds, we find that cytisine makes a second cation-π interaction 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-π interaction, 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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| Authors | Annet E M Blom, Hugo Rego Campello, Henry A Lester, Timothy Gallagher, Dennis A Dougherty |
| Journal | Journal of the American Chemical Society (J Am Chem Soc) Vol. 141 Issue 40 Pg. 15840-15849 (10 09 2019) ISSN: 1520-5126 [Electronic] United States |
| PMID | 31518499 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't) |
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