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

Kathleen M. Gilbert, Terrence L. Boos, Christina M. Dersch, Elisabeth Greiner, Arthur E. Jacobson, David Lewis, Dorota Matecka, Thomas E. Prisinzano, Ying Zhang, Richard B. Rothman, Kenner C. Rice, Carol A. Venanzi

Research output: Contribution to journalArticlepeer-review

14 Scopus citations


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 pKi (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 q2 = 0.508, standard error of prediction = 0.601, two components, r2 = 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 pKi (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.

Original languageEnglish
Pages (from-to)1146-1159
Number of pages14
JournalBioorganic and Medicinal Chemistry
Issue number2
StatePublished - Jan 15 2007

Bibliographical note

Funding Information:
This work was supported in part by grant DA018153 to C.A.V. from the National Institutes of Health (NIH). The authors at the Laboratory of Medicinal Chemistry, NIDDK, NIH, thank the National Institute on Drug Abuse for partial financial support of their research program. K.M.G. acknowledges the support of NIH Ruth L. Kirschstein NRSA Individual Predoctoral Fellowship DA15555. The authors wish to thank Dr. Christopher van Dyke, Tripos, Inc. for helpful discussions.


  • 3D-QSAR
  • Cocaine addiction
  • DAT/SERT selectivity
  • Dopamine transporter
  • GBR 12909
  • Validation

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry


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