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DAT/SERT selectivity of flexible GBR 12909 analogs modeled using 3D-QSAR methods.

ABSTRACT: 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.

SUBMITTER: Gilbert KM

PROVIDER: S-EPMC2259226 | biostudies-literature | 2007 Jan

REPOSITORIES: biostudies-literature

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DAT/SERT selectivity of flexible GBR 12909 analogs modeled using 3D-QSAR methods.

Gilbert Kathleen M KM Boos Terrence L TL Dersch Christina M CM Greiner Elisabeth E Jacobson Arthur E AE Lewis David D Matecka Dorota D Prisinzano Thomas E TE Zhang Ying Y Rothman Richard B RB Rice Kenner C KC Venanzi Carol A CA

Bioorganic & medicinal chemistry 20061001 2

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) ...[more]

PMID: 17127069

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DAT/SERT selectivity of flexible GBR 12909 analogs modeled using 3D-QSAR methods.

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DAT/SERT selectivity of flexible GBR 12909 analogs modeled using 3D-QSAR methods.

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