Synthesis of 3 beta-aryl-8-azabicyclo[3.2.1]octanes with high binding affinities and selectivities for the serotonin transporter site

J Med Chem. 1996 Jun 21;39(13):2554-8. doi: 10.1021/jm9600508.

Abstract

A novel entry to tropane analogs of cocaine was developed based on the reaction of rhodium-stabilized vinylcarbenoids with pyrroles. These analogs were tested in binding to dopamine, serotonin (5-HT), and norepinephrine 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 and an ethyl ketone moiety was present at the 2 position. By appropriate modification of the aryl and nitrogen substituents, highly potent and 5-HT selective tropanes were prepared. The most potent and selective compound was 3 beta-[4-(1-methylethenyl)phenyl]-2 beta-propanoyl-8-azabicyclo[3.2.1]octane (13b) which had a Ki of 0.1 nM at 5-HT transporters and was 150 times more potent at 5-HT vs dopamine transporters and almost 1000 times more potent at 5-HT vs norepinephrine transporters.

Publication types

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

MeSH terms

  • Animals
  • Binding, Competitive
  • Carrier Proteins / metabolism
  • Cocaine / analogs & derivatives
  • Cocaine / metabolism
  • Corpus Striatum / metabolism
  • Dopamine
  • Dopamine Plasma Membrane Transport Proteins
  • Fluoxetine / analogs & derivatives
  • Fluoxetine / metabolism
  • Frontal Lobe / metabolism
  • Magnetic Resonance Spectroscopy
  • Membrane Glycoproteins / metabolism
  • Membrane Transport Proteins*
  • Molecular Structure
  • Nerve Tissue Proteins*
  • Norepinephrine / metabolism
  • Norepinephrine Plasma Membrane Transport Proteins
  • Paroxetine / metabolism
  • Rats
  • Selective Serotonin Reuptake Inhibitors / metabolism
  • Serotonin / metabolism*
  • Serotonin Plasma Membrane Transport Proteins
  • Structure-Activity Relationship
  • Symporters*
  • Tropanes / chemical synthesis*
  • Tropanes / chemistry
  • Tropanes / metabolism
  • Tropanes / pharmacology*

Substances

  • Carrier Proteins
  • Dopamine Plasma Membrane Transport Proteins
  • Membrane Glycoproteins
  • Membrane Transport Proteins
  • Nerve Tissue Proteins
  • Norepinephrine Plasma Membrane Transport Proteins
  • Serotonin Plasma Membrane Transport Proteins
  • Serotonin Uptake Inhibitors
  • Slc6a2 protein, rat
  • Slc6a4 protein, rat
  • Symporters
  • Tropanes
  • Fluoxetine
  • nisoxetine
  • Serotonin
  • Paroxetine
  • 2beta-carbomethoxy-3beta-(4-iodophenyl)tropane
  • Cocaine
  • Dopamine
  • Norepinephrine