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

Authors

Kathleen M. Gilbert, New Jersey Institute of Technology
Terrence L. Boos, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Christina M. Dersch, National Institute on Drug Abuse (NIDA)
Elisabeth Greiner, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Arthur E. Jacobson, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
David Lewis, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Dorota Matecka, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Thomas E. Prisinzano, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Ying Zhang, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Richard B. Rothman, National Institute on Drug Abuse (NIDA)
Kenner C. Rice, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Carol A. Venanzi, New Jersey Institute of Technology

Document Type

Article

Publication Date

1-15-2007

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 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. © 2006 Elsevier Ltd. All rights reserved.

Identifier

33845431416 (Scopus)

Publication Title

Bioorganic and Medicinal Chemistry

External Full Text Location

https://doi.org/10.1016/j.bmc.2006.09.070

ISSN

09680896

PubMed ID

17127069

First Page

1146

Last Page

1159

Issue

2

Volume

15

Grant

Z01DA000521

Fund Ref

National Institutes of Health

Recommended Citation

Gilbert, Kathleen M.; Boos, Terrence L.; Dersch, Christina M.; Greiner, Elisabeth; Jacobson, Arthur E.; Lewis, David; Matecka, Dorota; Prisinzano, Thomas E.; Zhang, Ying; Rothman, Richard B.; Rice, Kenner C.; and Venanzi, Carol A., "DAT/SERT selectivity of flexible GBR 12909 analogs modeled using 3D-QSAR methods" (2007). Faculty Publications. 13567.
https://digitalcommons.njit.edu/fac_pubs/13567