Quantitative structure-agonist activity relationship of capsaicin analogues.

The MULTIple Computer Automated Structure Evaluation (MULTICASE) methodology has been used to study the quantitative structure-agonist activity relationship of a series of capsaicin agonists. A number of substructures and physiochemical properties of capsaicin analogues were identified as being responsible for high agonist potency. The optimal log P value for the agonist potency as estimated from QSAR analysis is 5.12. It was also found that a cluster of inactive molecules in the database have lipophilicity values below 2.94. Molecular modeling was employed to elucidate the detailed structural features of the pharmacophore of capsaicin analogues. Systematic conformational analysis has shown that the activity of capsaicin analogues strongly depends upon their ability to reach the required conformational profile. Based upon these observations, a three-dimensional pharmacophore model for the capsaicin-receptor interactions is proposed.