title: 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.
authors.affiliation: Department of Chemistry and Environmental Science, New Jersey Institute of Technology, University Heights, Newark, NJ 07102, USA.
authors.forename: Kathleen M
authors.initials: KM
authors.lastname: Gilbert
authors.forename: Terrence L
authors.initials: TL
authors.lastname: Boos
authors.forename: Christina M
authors.initials: CM
authors.lastname: Dersch
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Greiner
authors.forename: Arthur E
authors.initials: AE
authors.lastname: Jacobson
authors.forename: David
authors.initials: D
authors.lastname: Lewis
authors.forename: Dorota
authors.initials: D
authors.lastname: Matecka
authors.forename: Thomas E
authors.initials: TE
authors.lastname: Prisinzano
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.forename: Richard B
authors.initials: RB
authors.lastname: Rothman
authors.forename: Kenner C
authors.initials: KC
authors.lastname: Rice
authors.forename: Carol A
authors.initials: CA
authors.lastname: Venanzi
mesh_terms: D016000:Cluster Analysis; D003198:Computer Simulation; D050483:Dopamine Plasma Membrane Transport Proteins / Q000187:drug effects / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D008958:Models, Molecular; D008968:Molecular Conformation; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry* / Q000494:pharmacology; D021281:Quantitative Structure-Activity Relationship; D015203:Reproducibility of Results
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D010879:Piperazines; C043425:vanoxerine