Cocaine inhibition of ligand binding at dopamine, norepinephrine and serotonin transporters: a structure-activity study

Life Sci. 1990;46(9):635-45. doi: 10.1016/0024-3205(90)90132-b.


Structure-activity relationships for cocaine and analog binding at the dopamine, norepinephrine and serotonin transporters were determined. Cocaine inhibition of ligand binding to each of these sites has a stereospecific requirement for the levorotatory isomer. Binding potencies of cocaine derivatives involving N-substitution, C2 and C3 substituent modifications, however, revealed differences in structure-activity relationships for cocaine binding at the transporters. Removal of the N-methyl groups produced little change in binding potency at the dopamine transporter site but produced increases in binding potency at norepinephrine and serotonin transporter sites. Changes in structure at the C2 substituent produced changes in binding potency at the dopamine transporter which were generally similar in direction, but not necessarily in magnitude at the norepinephrine and serotonin transporters. Modifications to the C3 substituent, especially substitution of a hydroxyl moiety, produce changes in affinity at norepinephrine and serotonin transporters which are much larger than those observed at dopamine transporters. In general, our results indicate that unique structural requirements exist for each transporter site, but that cocaine binding at norepinephrine and dopamine transporters can be described by more similar structure-activity relationships than those found for the serotonin transporter. Requirements for cocaine binding to the dopamine transporter, which we have previously shown to be associated with the reinforcing effects of cocaine, include levorotatory stereospecificity, the benzene ring at C3, at least some portions of the tropane ring, and the presence of the C2 methyl ester group in the beta conformation.

MeSH terms

  • Animals
  • Binding Sites
  • Biological Transport / drug effects
  • Carrier Proteins / metabolism
  • Cocaine / metabolism
  • Cocaine / pharmacology*
  • Dopamine / metabolism*
  • Ligands
  • Male
  • Norepinephrine / metabolism*
  • Rats
  • Rats, Inbred Strains
  • Serotonin / metabolism*
  • Structure-Activity Relationship


  • Carrier Proteins
  • Ligands
  • Serotonin
  • Cocaine
  • Dopamine
  • Norepinephrine