Novel N-substituted 3 alpha-[bis(4'-fluorophenyl)methoxy]tropane analogues: selective ligands for the dopamine transporter

J Med Chem. 1997 Dec 19;40(26):4329-39. doi: 10.1021/jm970525a.


A series of N-substituted 3 alpha-[bis(4'-fluorophenyl)methoxy]tropane analogues has been prepared that function as dopamine uptake inhibitors. The N-methylated analogue of this series had a significantly higher affinity for the dopamine transporter than the parent compound, N-methyl-3 alpha- (diphenylmethoxy)tropane (benztropine, Cogentin). Yet like the parent compound, it retained high affinity for muscarinic receptors. A series of N-substituted compounds were prepared from nor-3 alpha-[bis(4'-fluorophenyl)methoxy]tropane via acylation followed by hydride reduction of the amide or by direct alkylation. All compounds containing a basic tropane nitrogen displaced [3H]WIN 35,428 at the dopamine transporter (Ki range = 8.5-634 nM) and blocked dopamine uptake (IC50 range = 10-371 nM) in rat caudate putamen, whereas ligands with a nonbasic nitrogen were virtually inactive. None of the compounds demonstrated high binding affinity at norepinephrine or serotonin transporters. Importantly, a separation of binding affinities for the dopamine transporter versus muscarinic m1 receptors was achieved by substitution of the N-methyl group with other N-alkyl or arylalkyl substituents (eg. n-butyl, allyl, benzyl, 3-phenylpropyl, etc.). Additionally, the most potent and selective analogue in this series at the dopamine transporter, N-(4"-phenyl-n-butyl)-3 alpha-[bis(4'-fluorophenyl)methoxy]tropane analogue failed to substitute for cocaine in rats trained to discriminate cocaine from saline. Potentially, new leads toward the development of a pharmacotherapeutic for cocaine abuse and other disorders affecting the dopamine transporter may be discovered.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Binding, Competitive
  • Brain / metabolism
  • Carrier Proteins / metabolism*
  • Cocaine / analogs & derivatives
  • Cocaine / metabolism
  • Cocaine / pharmacology
  • Crystallography, X-Ray
  • Dopamine / metabolism
  • Dopamine Plasma Membrane Transport Proteins
  • Dopamine Uptake Inhibitors / chemical synthesis*
  • Dopamine Uptake Inhibitors / chemistry
  • Dopamine Uptake Inhibitors / metabolism
  • Dopamine Uptake Inhibitors / pharmacology
  • Ligands
  • Male
  • Membrane Glycoproteins*
  • Membrane Transport Proteins*
  • Mice
  • Models, Molecular
  • Molecular Structure
  • Motor Activity / drug effects
  • Nerve Tissue Proteins*
  • Rats
  • Receptors, Muscarinic / metabolism
  • Structure-Activity Relationship
  • Tropanes / chemical synthesis*
  • Tropanes / chemistry
  • Tropanes / metabolism
  • Tropanes / pharmacology


  • Carrier Proteins
  • Dopamine Plasma Membrane Transport Proteins
  • Dopamine Uptake Inhibitors
  • Ligands
  • Membrane Glycoproteins
  • Membrane Transport Proteins
  • Nerve Tissue Proteins
  • Receptors, Muscarinic
  • Tropanes
  • (1R-(exo,exo))-3-(4-fluorophenyl)-8-methyl-8- azabicyclo(3.2.1)octane-2-carboxylic acid, methyl ester
  • Cocaine
  • Dopamine