Discovery of 8-azabicyclo[3.2.1]octan-3-yloxy-benzamides as selective antagonists of the kappa opioid receptor. Part 1

Bioorg Med Chem Lett. 2010 Oct 1;20(19):5847-52. doi: 10.1016/j.bmcl.2010.07.113. Epub 2010 Jul 30.

Abstract

Initial high throughput screening efforts identified highly potent and selective kappa opioid receptor antagonist 3 (κ IC(50)=77 nM; μ:κ and δ:κ IC(50) ratios>400) which lacked CNS exposure in vivo. Modification of this scaffold resulted in development of a series of 8-azabicyclo[3.2.1]octan-3-yloxy-benzamides showing potent and selectivity κ antagonism as well as good brain exposure. Analog 6c (κ IC(50)=20 nM; μ:κ=36, δ:κ=415) was also shown to reverse κ-agonist induced rat diuresis in vivo.

MeSH terms

  • Animals
  • Benzamides / chemical synthesis
  • Benzamides / chemistry*
  • Benzamides / pharmacokinetics
  • Cell Line, Tumor
  • Diuresis / drug effects
  • Drug Evaluation, Preclinical
  • High-Throughput Screening Assays
  • Humans
  • Microsomes, Liver / metabolism
  • Rats
  • Receptors, Opioid, kappa / antagonists & inhibitors*
  • Receptors, Opioid, kappa / metabolism
  • Structure-Activity Relationship
  • Tropanes / chemical synthesis
  • Tropanes / chemistry*
  • Tropanes / pharmacokinetics

Substances

  • Benzamides
  • Receptors, Opioid, kappa
  • Tropanes