Potency enhancement of the κ-opioid receptor antagonist probe ML140 through sulfonamide constraint utilizing a tetrahydroisoquinoline motif

Bioorg Med Chem. 2015 Jul 15;23(14):3948-56. doi: 10.1016/j.bmc.2014.12.033. Epub 2014 Dec 23.

Abstract

Optimization of the sulfonamide-based kappa opioid receptor (KOR) antagonist probe molecule ML140 through constraint of the sulfonamide nitrogen within a tetrahydroisoquinoline moiety afforded a marked increase in potency. This strategy, when combined with additional structure-activity relationship exploration, has led to a compound only six-fold less potent than norBNI, a widely utilized KOR antagonist tool compound, but significantly more synthetically accessible. The new optimized probe is suitably potent for use as an in vivo tool to investigate the therapeutic potential of KOR antagonists.

Keywords: Antagonist; Kappa opioid receptor; Molecular constraint; Potency enhancement; Tetrahydroisoquinoline.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Arrestins / metabolism
  • Benzamides / chemistry
  • Benzamides / pharmacology*
  • CHO Cells
  • Chemistry Techniques, Synthetic
  • Cricetulus
  • Drug Evaluation, Preclinical / methods
  • Guanosine 5'-O-(3-Thiotriphosphate) / metabolism
  • Humans
  • Naltrexone / analogs & derivatives
  • Naltrexone / chemistry
  • Narcotic Antagonists / chemistry
  • Narcotic Antagonists / pharmacology
  • Receptors, Opioid, kappa / antagonists & inhibitors*
  • Receptors, Opioid, kappa / genetics
  • Structure-Activity Relationship*
  • Sulfonamides / chemistry
  • Sulfonamides / pharmacology*
  • Tetrahydroisoquinolines / chemistry
  • beta-Arrestins

Substances

  • Arrestins
  • Benzamides
  • ML140 compound
  • Narcotic Antagonists
  • Receptors, Opioid, kappa
  • Sulfonamides
  • Tetrahydroisoquinolines
  • beta-Arrestins
  • norbinaltorphimine
  • Guanosine 5'-O-(3-Thiotriphosphate)
  • Naltrexone