CaltechAUTHORS
  A Caltech Library Service

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

Blom, Annet E. M. and Rego Campello, Hugo and Lester, Henry A. and Gallagher, Timothy and Dougherty, Dennis A. (2019) Probing Binding Interactions of Cytisine Derivatives to the α4β2 Nicotinic Acetylcholine Receptor. Journal of the American Chemical Society, 141 (40). pp. 15840-15849. ISSN 0002-7863. doi:10.1021/jacs.9b06580. https://resolver.caltech.edu/CaltechAUTHORS:20190916-135720189

[img] PDF - Accepted Version
See Usage Policy.

2MB
[img] PDF (Figures S1–S5 and Tables S1–S13, as well as procedures for the syntheses of cytisine derivatives and their 1H and 13C NMR data) - Supplemental Material
See Usage Policy.

1MB

Use this Persistent URL to link to this item: https://resolver.caltech.edu/CaltechAUTHORS:20190916-135720189

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.


Item Type:Article
Related URLs:
URLURL TypeDescription
https://doi.org/10.1021/jacs.9b06580DOIArticle
ORCID:
AuthorORCID
Blom, Annet E. M.0000-0002-7441-4893
Rego Campello, Hugo0000-0001-8588-0198
Lester, Henry A.0000-0002-5470-5255
Gallagher, Timothy0000-0002-3544-327X
Dougherty, Dennis A.0000-0003-1464-2461
Additional Information:© 2019 American Chemical Society. Received: June 20, 2019; Published: September 13, 2019. We thank Dr. Aurelian Honraedt for help in the synthesis of the derivatives. We thank Dr. Justin A. Hilf and Prof. Brian Stoltz for their assistance in calculating logD values. We thank Achieve Life Sciences for their generous gift of (−)-cytisine, and the University of Bristol and Engineering and Physical Sciences Research Council (No. EP/N024117/1) for financial support. This work was partially supported by funds provided by The Regents of the University of California, Research Grants Program Office, Tobacco Related Disease Research Program (Grant No. T29IR0445). The opinions, findings, and conclusions herein are those of the authors and do not necessarily represent those of The Regents of the University of California, or any of its programs. Author Contributions: All authors have revised and given approval to the final version of the manuscript. The authors declare no competing financial interest.
Funders:
Funding AgencyGrant Number
University of BristolUNSPECIFIED
Engineering and Physical Sciences Research Council (EPSRC)EP/N024117/1
California Tobacco-Related Disease Research ProgramT29IR0445
Issue or Number:40
DOI:10.1021/jacs.9b06580
Record Number:CaltechAUTHORS:20190916-135720189
Persistent URL:https://resolver.caltech.edu/CaltechAUTHORS:20190916-135720189
Official Citation:Probing Binding Interactions of Cytisine Derivatives to the α4β2 Nicotinic Acetylcholine Receptor. Annet E.M. Blom, Hugo Rego Campello, Henry A. Lester, Timothy Gallagher, and Dennis A. Dougherty. Journal of the American Chemical Society 2019 141 (40), 15840-15849. DOI: 10.1021/jacs.9b06580
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:98658
Collection:CaltechAUTHORS
Deposited By: Tony Diaz
Deposited On:16 Sep 2019 21:14
Last Modified:16 Nov 2021 17:40

Repository Staff Only: item control page