Novel Dimethyltyrosine-Tetrahydroisoquinoline Peptidomimetics with Aromatic Tetrahydroisoquinoline Substitutions Show in Vitro Kappa and Mu Opioid Receptor Agonism

ACS Chem Neurosci. 2019 Aug 21;10(8):3682-3689. doi: 10.1021/acschemneuro.9b00250. Epub 2019 Jul 1.

Abstract

The dimethyltyrosine-tetrahydroisoquinoline (Dmt-Tiq) scaffold was originally developed in the production of selective delta opioid receptor (DOR) antagonists. Installation of a 7-benzyl pendant on the tetrahydroisoquinoline core of this classic opioid scaffold introduced kappa opioid receptor (KOR) agonism. Further modification of this pendant resulted in retention of KOR agonism and the addition of mu opioid receptor (MOR) partial agonism, a bifunctional profile with potential to be used in the treatment of cocaine addiction.

Keywords: cocaine addiction; dimethyltyrosine−tetrahydroisoquinoline; multifunctional ligands; opioids; peptidomimetics; synthesis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Cell Line
  • Peptidomimetics / pharmacology*
  • Rats
  • Receptors, Opioid, kappa / agonists*
  • Receptors, Opioid, mu / agonists*
  • Structure-Activity Relationship
  • Tetrahydroisoquinolines / pharmacology*

Substances

  • Peptidomimetics
  • Receptors, Opioid, kappa
  • Receptors, Opioid, mu
  • Tetrahydroisoquinolines