Structure-activity relationships at monoamine transporters for a series of N-substituted 3alpha-(bis[4-fluorophenyl]methoxy)tropanes: comparative molecular field analysis, synthesis, and pharmacological evaluation.

  • Kulkarni S
  • Grundt P
  • Kopajtic T
 et al. 
  • 1


    Mendeley users who have this article in their library.
  • N/A


    Citations of this article.


The development of structure-activity relationships (SAR) with divergent classes of monoamine transporter ligands and comparison of their effects in animal models of cocaine abuse have provided insight into the complex relationship among structure, binding profiles, and behavioral activity. Many 3alpha-(diphenylmethoxy)tropane (benztropine) analogues are potent dopamine uptake inhibitors but exhibit behavioral profiles that differ from those of cocaine and other compounds in this class. One of the most potent and dopamine transporter (DAT) selective N-substituted benztropine analogues (N-(4-phenyl-n-butyl)-3alpha-(bis[4-fluorophenyl]methoxy)tropane, 1c) is devoid of cocaine-like behaviors in rodent models but is also highly lipophilic (cLogD = 5.01), which compromises its water solubility and may adversely affect its pharmacokinetic properties. To further explore the SAR in this series and ultimately to design dopamine uptake inhibitors with favorable lipophilicities for drug development, a comparative molecular field analysis (CoMFA) was performed on a set of benztropine analogues previously synthesized in our laboratory. The CoMFA field analysis on the statistically significant (r2(cv) = 0.632; r2(ncv) = 0.917) models provided valuable insight into the structural features required for optimal binding to the DAT, which was used to design a series of novel benztropine analogues with heteroatom substitutions at the tropane N-8. These compounds were evaluated for binding at DAT, serotonin (SERT) and norepinephrine (NET) transporters, and muscarinic M1 receptors in rat brain. Inhibition of [3H]DA uptake in synaptosomes was also evaluated. Most of the analogues showed high DAT affinity (12-50 nM), selectivity (10- to 120-fold), potent inhibition of dopamine uptake, and lower lipophilicities as predicted by cLogD values.

Author-supplied keywords

  • Animals
  • Brain
  • Carrier Proteins
  • Dopamine Plasma Membrane Transport Proteins
  • Dopamine Uptake Inhibitors
  • In Vitro Techniques
  • Male
  • Membrane Glycoproteins
  • Membrane Transport Proteins
  • Models, Molecular
  • Nerve Tissue Proteins
  • Norepinephrine Plasma Membrane Transport Proteins
  • Protein Binding
  • Quantitative Structure-Activity Relationship
  • Radioligand Assay
  • Rats
  • Rats, Sprague-Dawley
  • Receptor, Muscarinic M1
  • Serotonin Plasma Membrane Transport Proteins
  • Symporters
  • Tropanes
  • chemical synthesis
  • chemistry
  • metabolism
  • pharmacology

Get free article suggestions today

Mendeley saves you time finding and organizing research

Sign up here
Already have an account ?Sign in

Find this document


  • Santosh S Kulkarni

  • Peter Grundt

  • Theresa Kopajtic

  • Jonathan L Katz

  • Amy Hauck Newman

Cite this document

Choose a citation style from the tabs below

Save time finding and organizing research with Mendeley

Sign up for free