Synthesis of 2 beta-acyl-3 beta-aryl-8-azabicyclo[3.2.1]octanes and their binding affinities at dopamine and serotonin transport sites in rat striatum and frontal cortex

J Med Chem. 1994 Apr 29;37(9):1262-8. doi: 10.1021/jm00035a005.


A novel entry to tropane analogs of cocaine was developed on the basis of the reaction of rhodium-stabilized vinylcarbenoids with pyrroles. These analogs were tested in binding to dopamine and serotonin (5-HT) transporters in membranes from rat striatum and frontal cortex. In all the analogs, the aryl group at the 3-position was directly bound to the tropane ring (as in WIN-35,428), and methyl or ethyl ketone moieties were present at the 2-position instead of the typical ester group. The series of analogs containing a 2-naphthyl group at the 3-position were most potent, with Ki values < 1 nM in binding to both dopamine and 5-HT transporters. Although the unsubstituted 2-naphthyl analog was nonselective at dopamine and 5-HT transport sites, other compounds were selective for either site. In general, compounds with relatively small substituents on the aromatic moiety (such as p-methyl or p-fluoro) were relatively selective for the dopamine transporters, while a p-isopropylphenyl derivative was selective for the 5-HT transport sites. This latter compound represents the first N-methyltropane derivative specific for 5-HT transporters. Resolution of two of the most significant analogs was achieved by HPLC on a chiral stationary phase; the active enantiomer of a 2-naphthyl analog exhibited Ki values of < 0.1 nM at both dopamine and 5-HT transporter sites.

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 Sites
  • Binding, Competitive
  • Carrier Proteins / metabolism*
  • Cocaine / analogs & derivatives*
  • Cocaine / metabolism
  • Corpus Striatum / metabolism*
  • Dopamine Plasma Membrane Transport Proteins
  • Frontal Lobe / metabolism*
  • Male
  • Membrane Glycoproteins / metabolism*
  • Membrane Transport Proteins*
  • Molecular Structure
  • Nerve Tissue Proteins*
  • Pyrroles / chemistry
  • Rats
  • Rats, Sprague-Dawley
  • Rhodium
  • Serotonin Plasma Membrane Transport Proteins
  • Structure-Activity Relationship
  • Tritium


  • Carrier Proteins
  • Dopamine Plasma Membrane Transport Proteins
  • Membrane Glycoproteins
  • Membrane Transport Proteins
  • Nerve Tissue Proteins
  • Pyrroles
  • Serotonin Plasma Membrane Transport Proteins
  • Slc6a4 protein, rat
  • Tritium
  • 2beta-carbomethoxy-3beta-(4-iodophenyl)tropane
  • Rhodium
  • Cocaine