N-modified analogues of cocaine: synthesis and inhibition of binding to the cocaine receptor

J Med Chem. 1992 Jan;35(1):141-4. doi: 10.1021/jm00079a018.


Cocaine methiodide (2), N-norcocaine (1b), N-benzyl-N-norcocaine (1c), and N-nor-N-acetylcocaine (1d) were synthesized and evaluated for their ability to inhibit binding of [3H]-3 beta-(4-fluorophenyl)tropane-2 beta-carboxylic acid methyl ester (WIN 35,428) to the cocaine receptor. The study showed that removal of the N-methyl group to give 1b, or replacement with the larger N-benzyl group to give 1c, has a relatively small effect on binding potency. In contrast, replacement of the N-methyl group by the acetyl moiety to give 1d, or the addition of a methyl group to give 2, reduces affinity for the receptor by a large factor. In order to gain preliminary information concerning the importance of the nitrogen location on the tropane ring system, the receptor binding affinity of 8-methyl-8-azabicyclo[3.2.1]octan-3 beta-ol benzoate (5, beta-tropacocaine) was compared to that of the isomeric 6-methyl-6-azabicyclo[3.2.1]octan-3 beta-ol benzoate (4d). The fact that both compounds have similar binding affinities for the cocaine receptor suggests that 3 beta-(benzoyloxy)-6-methyl-6-azabicyclo[3.2.1] octane-2-carboxylic acid methyl ester, which is isomeric with cocaine, may possess binding potency similar to cocaine.

Publication types

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

MeSH terms

  • Analgesics / chemical synthesis*
  • Analgesics / chemistry
  • Analgesics / pharmacology
  • Animals
  • Binding, Competitive
  • Carrier Proteins*
  • Cocaine / analogs & derivatives*
  • Corpus Striatum / drug effects
  • Corpus Striatum / metabolism
  • Male
  • Rats
  • Rats, Inbred Strains
  • Receptors, Drug / drug effects*
  • Receptors, Drug / metabolism
  • Structure-Activity Relationship


  • Analgesics
  • Carrier Proteins
  • Receptors, Drug
  • cocaine receptor
  • Cocaine