Deltorphin II analogues with 6-hydroxy-2-aminotetralin-2-carboxylic acid in position 1

J Med Chem. 2000 Apr 6;43(7):1359-66. doi: 10.1021/jm9911534.

Abstract

Two approaches to the design of very active and highly selective delta opioid peptides were used to obtain new deltorphin analogues with altered hydrophobic and stereoelectronic properties. Deltorphin II analogues were synthesized with the substitution of Ile instead of Val at positions 5 and 6 in the address domain and 6-hydroxy-2-aminotetralin-2-carboxylic acid (Hat) instead of Tyr(1) in the message domain. In the radioreceptor-binding studies, in which type-specific tritiated opioid ligands were used, (R)- and (S)-Hat-deltorphins exhibited similar K(i) values, revealing high delta selectivity. The peptides displayed agonist properties in the in vitro bioassay, with IC(50) values in the subnanomolar range in the mouse vas deferens assay and in the micromolar or higher range in the guinea pig ileum assay, again demonstrating a high selectivity toward delta receptors. The agonist property of the new ligands was confirmed by means of [(35)S]GTPgammaS-binding experiments in membranes of the rat frontal cortex.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 2-Naphthylamine / analogs & derivatives
  • 2-Naphthylamine / chemical synthesis*
  • 2-Naphthylamine / chemistry
  • 2-Naphthylamine / pharmacology
  • Amino Acids / chemical synthesis*
  • Amino Acids / chemistry
  • Amino Acids / pharmacology
  • Animals
  • Electric Stimulation
  • Frontal Lobe / metabolism
  • Guinea Pigs
  • Ileum / drug effects
  • Ileum / physiology
  • In Vitro Techniques
  • Magnetic Resonance Spectroscopy
  • Male
  • Mice
  • Models, Molecular
  • Molecular Conformation
  • Muscle Contraction / drug effects
  • Muscle, Smooth / drug effects
  • Muscle, Smooth / physiology
  • Oligopeptides / chemical synthesis*
  • Oligopeptides / chemistry
  • Oligopeptides / pharmacology
  • Radioligand Assay
  • Rats
  • Rats, Wistar
  • Receptors, Opioid, delta / agonists
  • Receptors, Opioid, delta / metabolism
  • Stereoisomerism
  • Structure-Activity Relationship
  • Vas Deferens / drug effects
  • Vas Deferens / physiology

Substances

  • 6-hydroxy-2-aminotetralin-2-carboxylic acid
  • Amino Acids
  • Oligopeptides
  • Receptors, Opioid, delta
  • deltorphin II, Ala(2)-
  • 2-Naphthylamine