Quantitative structure-activity relationships of phenyltropanes as inhibitors of three monoamine transporters: Classical and CoMFA studies

The inhibitory activity values (IC50) Of 54 phenyltropanes at the DA, 5-HT and NA transporters were quantitatively examined by use of different QSAR-t echniques and PLS-1. All models were validated via leave-one-out cross-vali dation. In addition, the 2D and 3D QSAR analyses were externally validated with a test set of 8 compounds based on design considerations. Free-Wilson analyses comprising all 62 compounds revealed the presence of a homogenous data set and a linear SAR for the above-mentioned transporters. Application of a VIP-guided variable selection procedure on an X-matrix containing 36 physicochemical and quantum mechanical parameters resulted in informative 2 D models that were simple to interpret. For purpose of comparison additiona l CoMFA models using the standard fields were constructed from a molecular alignment maximizing the similarity of molecular shape and electrostatic po tential. Highly significant models with good fitting and predictive abiliti es were developed for each transporter, The major structural requirements r evealed from the CoMFA analyses were in good agreement with the findings of the individual 2D analyses. Whereas the DA and NA transporters are sensiti ve to steric bulk arising from the 3 beta-phenyl ring, large substituents R -2 in position C2 of the tropane ring or a N-methyl group instead of a hydr ogen decrease binding affinity to the NA and 5-HT transporters. The models obtained suggest a close similarity between the examined transporters in te rms of binding interaction. A comparison of the CoMFA contour maps provides a rational basis for the design of selective ligands.