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Conformational analysis of piperazine and piperidine analogs of GBR 12909: stochastic approach to evaluating the effects of force fields and solvent

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Abstract

Analogs of the flexible dopamine reuptake inhibitor, GBR 12909 (1), may have potential utility in the treatment of cocaine abuse. As a first step in the 3D-QSAR modeling of the dopamine transporter (DAT)/serotonin transporter (SERT) selectivity of these compounds, we carried out conformational analyses of two analogs of 1: a piperazine (2) and a related piperidine (3). Ensembles of conformers consisting of local minima on the potential energy surface of the molecule were generated in the vacuum phase and in implicit solvent by random search conformational analysis using the Tripos and MMFF94 force fields. Some differences were noted in the conformer populations due to differences in the treatment of the tertiary amine nitrogen and ether oxygen atom types by the force fields. The force fields also differed in their descriptions of internal rotation around the C(sp 3)–O(sp 3) bond proximal to the bisphenyl moiety. Molecular orbital calculations at the HF/6-31G(d) and B3LYP/6-31G(d) levels of C–O internal rotation in model compound (5), designed to model the effect of the proximity of the bisphenyl group on C-O internal rotation, showed a broad region of low energy between −60° to 60° with minima at both −60° and 30° and a low rotational barrier at 0°, in closer agreement with the MMFF94 results than the Tripos results. Molecular mechanics calculations on model compound (6) showed that the MMFF94 force field was much more sensitive than the Tripos force field to the effects of the bisphenyl moiety on C–O internal rotation.

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Acknowledgments

This work was supported in part by grant DA018153 to C.A.V. from the National Institutes of Health (NIH). K.M.G. acknowledges the support of Ruth L. Kirschstein National Research Service Award Individual Predoctoral Fellowship DA015555 from NIH. The authors would like to thank Jeelum Naik, Eun Kim, and Anuj Kumar for assistance with some aspects of the calculations.

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Author notes

  1. Deepangi Pandit

    Present address: BioMaPS Institute for Quantitative Biology, Rutgers, the State University of New Jersey, 610 Taylor Road, Piscataway, NJ, 08854-8087, USA

  2. Milind Misra

    Present address: Multiscale Dynamic Materials Modeling Department, Sandia National Laboratories, Albuquerque, NM, 87185-1413, USA

Authors and Affiliations

  1. Department of Chemistry and Environmental Science, New Jersey Institute of Technology, 323 King Blvd., Newark, NJ, 07102-1982, USA

    Deepangi Pandit, Milind Misra, Kathleen M. Gilbert, William J. Skawinski & Carol A. Venanzi

  2. Department of Computer Science, New Jersey Institute of Technology, 323 King Blvd., Newark, NJ, 07102-1982, USA

    William Roosma

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  1. Deepangi Pandit
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Correspondence to Carol A. Venanzi.

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Pandit, D., Roosma, W., Misra, M. et al. Conformational analysis of piperazine and piperidine analogs of GBR 12909: stochastic approach to evaluating the effects of force fields and solvent. J Mol Model 17, 181–200 (2011). https://doi.org/10.1007/s00894-010-0712-x

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