Monoamine transporter binding, locomotor activity, and drug discrimination properties of 3-(4-substituted-phenyl)tropane-2-carboxylic acid methyl ester isomers

J Med Chem. 2004 Dec 2;47(25):6401-9. doi: 10.1021/jm0401311.


The monoamine transporter binding properties, gross behavior, and locomotor activity effects in mice and drug discrimination results in cocaine-trained rats of the 2 beta,3beta-, 2 beta,3 alpha-, 2 alpha,3beta-, and 2 alpha,3 alpha-isomers of several 3-(4-substituted-phenyl)tropane carboxylic acid methyl esters were compared (2a-f, 3a-f, 4a-f, and 5b,c). The 2 beta,3beta-isomer showed the highest affinity for the dopamine transporter (DAT), and the 2 beta,3 alpha-isomer showed the next highest affinity. The order of potency for the 2 beta,3beta-isomer is 4'-chloro (2c) = 4'-iodo (2e) > 4'-bromo (2d) = 4'-methyl (2f) > 4'-fluoro (2b) > 4'-hydrogen (2a). In the case of the 2 beta,3 alpha-isomer, the order of affinity was 4'-bromo (3d) > 4'-iodo (3e) = 4'- chloro (3c) > 4'-methyl (3f) > 4'-fluoro (3b) > 4'-hydrogen (3a). The 4'-hydrogen, 4'-fluoro, and 4'-methyl 2 alpha,3beta-isomers, 4a, 4b, and 4f, had the lowest affinity for the DAT. While most of the compounds showed their highest affinity at the DAT, none were selective relative to the other two monoamine transporters. In general, the 2 alpha,3 alpha- and 2 alpha,3beta-isomers were more toxic (death and convulsions) than the 2 beta,3beta- and 2 beta,3 alpha-isomers. With the exception of the 2 alpha,3 alpha-isomers, all compounds produced the locomotor activity stimulation typical of dopaminergic drugs. The ED(50) ranges for the 2 beta,3beta- (2a-f), 2 beta,3 alpha- (3a-f), and 2 alpha,3beta-isomers (4a-f) in the locomotor assay were 0.1-1.2, 6.6-21.8, and 2.4-11.7 mg/kg, respectively. With the exception of the 2 alpha,3 alpha-isomer, all compounds generalized to cocaine. The 2 beta,3beta-isomers were at least 10-fold more potent than cocaine and the other three sets of isomers in this test.

Publication types

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

MeSH terms

  • Animals
  • Binding, Competitive
  • Central Nervous System Stimulants / pharmacology
  • Cocaine / pharmacology
  • Discrimination Learning / drug effects
  • Discrimination, Psychological / drug effects*
  • Dopamine Plasma Membrane Transport Proteins
  • Esters
  • Isomerism
  • Male
  • Membrane Glycoproteins / metabolism*
  • Membrane Transport Proteins / metabolism*
  • Mice
  • Motor Activity / drug effects*
  • Nerve Tissue Proteins / metabolism*
  • Norepinephrine Plasma Membrane Transport Proteins
  • Radioligand Assay
  • Rats
  • Rats, Sprague-Dawley
  • Serotonin Plasma Membrane Transport Proteins
  • Structure-Activity Relationship
  • Symporters / metabolism*
  • Tropanes / chemical synthesis*
  • Tropanes / chemistry
  • Tropanes / pharmacology


  • Central Nervous System Stimulants
  • Dopamine Plasma Membrane Transport Proteins
  • Esters
  • Membrane Glycoproteins
  • Membrane Transport Proteins
  • Nerve Tissue Proteins
  • Norepinephrine Plasma Membrane Transport Proteins
  • Serotonin Plasma Membrane Transport Proteins
  • Slc6a2 protein, mouse
  • Slc6a2 protein, rat
  • Slc6a3 protein, mouse
  • Slc6a3 protein, rat
  • Slc6a4 protein, mouse
  • Slc6a4 protein, rat
  • Symporters
  • Tropanes
  • Cocaine