Evaluation of the odor activity of pyrazine derivatives using structural and electronic parameters derived from conformational study by molecular mechanics (MM3) and ab initio calculations

The conformational and electronic properties of the odor compounds, pyrazine and its derivatives, were investigated by molecular mechanics (MM3) and ab initio molecular orbital calculations in order to evaluate an odor activity. The calculated results have suggested that the essential factors to give rise to the odor activity are the presence of the lone-pair orbital on the nitrogen atom with an appropriate orientation (electronic interaction) and the conformation of the substituents attached in the pyrazine ring relative to the direction of lone-pair orbital on the nitrogen atom (molecular shape fitting to olfactory receptor site). The lone-pair orbital, which extends outside the pyrazine ring plane, is important to interact with the functional groups located at the olfactory receptor site. The pyrazine derivatives where alkyl substituents are appropriately oriented perpendicularly against the pyrazine ring are inclined to increase an odor activity. In order to evaluate an odor activity quantitatively, we used an index, the difference of the van der Waals volume (ΔvdW/pocketV), as a structural descriptor. The regression equation revealed that this descriptor enabled us to predict odor activities of pyrazine derivatives.