Chemistry - A European Journal
Chemistry - A European Journal
5 years ago

Structural Studies of Nicotinoids: Cotinine versus Nicotine

Structural Studies of Nicotinoids: Cotinine versus Nicotine
José A. Fernández, Emilio J. Cocinero, Francisco J. Basterretxea, Cristóbal Pérez, Elena Caballero-Mancebo, Iciar Uriarte, Alberto Lesarri
Nicotinoids are agonists of the acetylcholine receptor (nAChR) and play important biochemical and pharmacological roles. Herein, we report on the structure and conformation of cotinine, and compare its molecular properties with the nicotine prototype, from which it only differs in the addition of a carbonyl group. This investigation included a theoretical survey of the effects of rotamerization of the pyridine moiety, the puckering of the pyrrolidinone ring and the internal rotation of the methyl group. The experimental work examined the rotational spectrum of the molecule in a supersonic expansion, using both broadband chirped-pulse excitation techniques and cavity microwave spectrometers. Two conformers were observed for cotinine, and the fine and hyperfine structures arising from the two quadrupolar 14N nuclei and the methyl internal rotor were fully analyzed. The two observed conformers share the same twisted conformation of the five-membered ring, but differ in a roughly 180° rotamerization around the C−C bond connecting the two rings. The energy barriers for the internal rotation of the methyl group in cotinine (4.55(4) and 4.64(3) kJ mol−1, respectively) are much lower than in nicotine (estimated in 16.5 kJ mol−1). The combination of different intramolecular electronic effects, hydrogen bonding and possible binding differences to receptor molecules arising from the carbonyl group could explain the lower affinity of cotinine for nAChRs. Through the smoke: The conformation of cotinine was probed under isolation conditions by microwave spectroscopy. Interesting results are revealed when compared to structurally related nicotine in terms of the ring conformation, internal methyl rotation, and intramolecular interactions.

Publisher URL: http://onlinelibrary.wiley.com/resolve/doi

DOI: 10.1002/chem.201700023

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