Structural Studies of Nicotinoids: Cotinine versus Nicotine

Area of Science:

• Molecular Spectroscopy
• Computational Chemistry
• Pharmacology

Background:

• Nicotinoids are key agonists of nicotinic acetylcholine receptors (nAChRs), crucial in biochemical and pharmacological processes.
• Cotinine, a major nicotine metabolite, differs structurally by a carbonyl group, potentially altering its molecular properties and receptor interactions.

Purpose of the Study:

• To elucidate the structure and conformation of cotinine.
• To compare the molecular properties of cotinine with nicotine, focusing on the impact of the carbonyl group.
• To investigate the conformational flexibility and internal rotation dynamics of cotinine.

Main Methods:

• Theoretical calculations exploring rotamerization, ring puckering, and methyl group rotation.
• Experimental rotational spectroscopy using chirped-pulse and cavity microwave techniques in supersonic expansion.
• Analysis of fine and hyperfine structures due to 14N nuclei and methyl internal rotation.

Main Results:

• Two distinct cotinine conformers were experimentally observed, both featuring a twisted pyrrolidinone ring.
• The conformers differ by a ~180° rotation around the bond connecting the pyridine and pyrrolidinone rings.
• Cotinine exhibits significantly lower methyl group internal rotation energy barriers (approx. 4.6 kJ/mol) compared to nicotine (approx. 16.5 kJ/mol).

Conclusions:

• The observed conformational differences and reduced rotational barriers in cotinine, attributed to the carbonyl group, may explain its lower affinity for nAChRs.
• Intramolecular electronic effects and potential hydrogen bonding associated with the carbonyl group likely influence cotinine's receptor binding profile.
• This study provides a detailed molecular understanding of cotinine's structure and dynamics, relevant for its pharmacological activity.