Abstract: The analgesic activities of four 3-methylfentanyl and eight ohmefentanyl optical isomers are very different. In seeking for the reason why a small change in structure leads to such a great difference in activity, we carried out quantum chemistry and QSAR investigations on these compounds. It was found that the spatial relationship between 3-methyl group and the anilidophenyl was most important. Other factors such as the net atomic charge on carbonyl oxygen and the configuration of 1-(-hydroxy also influenced the activities. PLS method was used for the construction of QSAR model. Using only 3 latent variables the correlation and predictive ability were quite satisfactory.

Key words: MNDO, QSAR, 3-Methylfentanyl derivatives, PLS