Synthesis of 3-carbamoylecgonine Methyl Ester Analogues as Inhibitors of Cocaine Binding and Dopamine Uptake

J Med Chem. 1991 Feb;34(2):702-5. doi: 10.1021/jm00106a035.

Abstract

Five (1R-2-exo-3-exo)-3-(N-phenylcarbamoyl)ecgonine methyl ester analogues were synthesized and characterized by 1H and 13C NMR, IR, and thermospray MS. The compounds were synthesized in two or three steps as (-)-stereoisomers from (-)-ecgonine in good yield (56% overall). These cocaine derivatives were assessed for their ability to inhibit [3H]cocaine binding to rat striatal tissue and to inhibit [3H]dopamine uptake into synaptosomes prepared from the same tissue. The most potent of the analogues was (1R-2-exo-3-exo)-2-(carbomethoxy)-8-methyl-8-azabicyclo[3.2.1]octyl 3-N-(3'-nitrophenyl)carbamate. IC50 values for inhibition of cocaine binding and dopamine uptake were 37 and 178 nM, respectively. Amino derivatives were less active than the nitro and (1R-2-exo-3-exo)-2-(carbomethoxy)-8-methyl-8-azabicyclo [3.2.1]octyl 3-N-(4'-aminophenyl)carbamate had the lowest affinity for the receptor with IC50 values of 63 and greater than 100 microM in the aforementioned assays, respectively.

Publication types

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

MeSH terms

  • Animals
  • Brain / metabolism
  • Carrier Proteins*
  • Chemical Phenomena
  • Chemistry
  • Cocaine / analogs & derivatives*
  • Cocaine / chemical synthesis
  • Cocaine / metabolism
  • Dopamine / metabolism*
  • Rats
  • Receptors, Drug / drug effects
  • Structure-Activity Relationship

Substances

  • Carrier Proteins
  • Receptors, Drug
  • cocaine receptor
  • Cocaine
  • Dopamine
  • ecgonine methyl ester