Potent μ-Opioid Receptor Agonists from Cyclic Peptides Tyr-c[D-Lys-Xxx-Tyr-Gly]: Synthesis, Biological, and Structural Evaluation

J Med Chem. 2016 Feb 11;59(3):1239-45. doi: 10.1021/acs.jmedchem.5b01899. Epub 2016 Jan 29.

Abstract

To optimize the structure of a μ-opioid receptor ligand, analogs H-Tyr-c[D-Lys-Xxx-Tyr-Gly] were synthesized and their biological activity was tested. The analog containing a Phe(3) was identified as not only exhibiting binding affinity 14-fold higher than the original hit but also producing agonist activity 3-fold more potent than morphine. NMR study suggested that a trans conformation at D-Lys(2)-Xxx(3) is crucial for these cyclic peptides to maintain high affinity, selectivity, and functional activity toward the μ-opioid receptor.

Publication types

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

MeSH terms

  • Dose-Response Relationship, Drug
  • Humans
  • Molecular Structure
  • Nuclear Magnetic Resonance, Biomolecular
  • Peptides, Cyclic / chemical synthesis*
  • Peptides, Cyclic / chemistry
  • Peptides, Cyclic / pharmacology*
  • Receptors, Opioid, mu / agonists*
  • Receptors, Opioid, mu / metabolism
  • Structure-Activity Relationship

Substances

  • Peptides, Cyclic
  • Receptors, Opioid, mu