The Nicotinic Agonist Cytisine: The Role of the NH···N Interaction

J Phys Chem Lett. 2022 Oct 27;13(42):9991-9996. doi: 10.1021/acs.jpclett.2c02021. Epub 2022 Oct 20.

Abstract

We report a detailed structural study of cytisine, an alkaloid used to help with smoking cessation, looking forward to unveiling its role as a nicotinic agonist. High-resolution rotational spectroscopy has allowed us to characterize two different conformers exhibiting axial and equatorial arrangements of the piperidinic NH group. Unexpectedly, the axial form has been found as the predominant configuration, in contrast to that observed for related molecules, such as piperidine. This anomalous behavior has been justified in terms of an intramolecular NH···N hydrogen bond. Moreover, this interaction justifies the overstabilization of the axial conformer over the equatorial one and is crucial for the mechanism of action of cytisine over the nicotinic receptor, further rationalizing its behavior as a nicotinic agonist.

MeSH terms

  • Alkaloids*
  • Nicotinic Agonists
  • Piperidines
  • Receptors, Nicotinic*

Substances

  • Nicotinic Agonists
  • cytisine
  • Alkaloids
  • Receptors, Nicotinic
  • Piperidines