| 17127069 |
Gilbert KM, Boos TL, Dersch CM, Greiner E, Jacobson AE, Lewis D, Matecka D, Prisinzano TE, Zhang Y, Rothman RB, Rice KC, Venanzi CA: DAT/SERT selectivity of flexible GBR 12909 analogs modeled using 3D-QSAR methods. Bioorg Med Chem. 2007 Jan 15;15(2):1146-59. Epub 2006 Oct 1.
The dopamine reuptake inhibitor GBR 12909 (1-{2-[bis (4-fluorophenyl) methoxy] ethyl}-4-(3-phenylpropyl) piperazine, 1) and its analogs have been developed as tools to test the hypothesis that selective dopamine transporter (DAT) inhibitors will be useful therapeutics for cocaine addiction. This 3D-QSAR study focuses on the effect of substitutions in the phenylpropyl region of 1. CoMFA and CoMSIA techniques were used to determine a predictive and stable model for the DAT/serotonin transporter (SERT) selectivity (represented by pK (i) (DAT/SERT)) of a set of flexible analogs of 1, most of which have eight rotatable bonds. In the absence of a rigid analog to use as a 3D-QSAR template, six conformational families of analogs were constructed from six pairs of piperazine and piperidine template conformers identified by hierarchical clustering as representative molecular conformations. Three models stable to y-value scrambling were identified after a comprehensive CoMFA and CoMSIA survey with Region Focusing. Test set correlation validation led to an acceptable model, with q (2)=0.508, standard error of prediction=0.601, two components, r (2)=0.685, standard error of estimate=0.481, F value=39, percent steric contribution=65, and percent electrostatic contribution=35. A CoMFA contour map identified areas of the molecule that affect pK (i) (DAT/SERT). This work outlines a protocol for deriving a stable and predictive model of the biological activity of a set of very flexible molecules. |
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