N-inversion-associated conformational dynamics is unusually rapid in morphine alkaloids

Area of Science:

• Organic Chemistry
• Computational Chemistry
• Pharmacology

Background:

• N-inversion-C-N rotation (NIR) is a key dynamic process in substituted piperidines.
• Morphine alkaloids like codeine and sinomenine possess a substituted piperidine core.
• Understanding NIR barriers is essential for elucidating molecular mechanisms of drug action.

Purpose of the Study:

• To investigate the unusually fast N-inversion-C-N rotation (NIR) in codeine and sinomenine.
• To determine the energy barrier for NIR in these N-methyl morphinan derivatives.
• To explore the relationship between NIR dynamics and morphine receptor activation.

Main Methods:

• (13)C Dynamic Nuclear Magnetic Resonance ((13)C DNMR) spectroscopy was employed to study NIR.
• Ab initio calculations, specifically at the B3LYP/6-31G(p)/GIAO level, were used to determine chemical shift differences.
• Line shape analysis, incorporating calculated Delta delta values, was applied to determine the NIR barrier.

Main Results:

• (13)C DNMR studies indicated unusually rapid NIR in codeine and sinomenine compared to other N-methyl piperidines.
• Ab initio calculations provided essential Delta delta values for line shape analysis.
• The NIR barrier for the studied morphinans was determined to be in the range of 25-27 kJ mol(-1) (6.0-6.5 kcal mol(-1)).

Conclusions:

• A low N-inversion-C-N rotation barrier was determined for codeine and sinomenine.
• This low barrier is hypothesized to be a significant factor in the activation of the morphine receptor.
• The study highlights the utility of combining experimental NMR data with computational chemistry for characterizing molecular dynamics.