QSAR study on dual SET and NET reuptake inhibitors: an insight into the structural requirement for antidepressant...

Monoamine transporters have emerged as important drug targets with a multitude of therapeutic potentials for their inhibitors. With the purpose of designing new chemical entities with enhanced inhibitory potencies against norepinephrine and serotonin transporters, the QSAR study carried out on N-arylmethylpiperidinamine derivatives as known inhibitors of these transporters is presented. The developed model was validated by standard QSAR parameters and through a detailed structural analysis on how it reproduces and explains the differences in the experimentally known activity data. The model showed a good correlative and predictive ability having a squared cross validated correlation co-efficient of 0.716 and 0.700 respectively for SET and NET inhibition. The squared conventional correlation coefficient was found to be 0.731 for SET antagonism and 0.777 for norepinephrine reuptake inhibition. The study confirmed that the serotonin reuptake inhibitory activity exhibited by the series is largely explained by steric factors of substituents emphasizing the role of size and shape of the inhibitors in making effective inhibitor-SET binding interactions whereas substituent lipophilicity was found to govern inhibitor-NET interaction chemistry. A detailed comparative investigation was made between the two models and the insights gleaned from the study could be usefully employed to design inhibitors with a much more enhanced potency and selectivity.