Probing opioid receptor interactions with azacycloalkane amino acids. Synthesis of a potent and selective ORL1 antagonist

J Med Chem. 2002 Nov 21;45(24):5353-7. doi: 10.1021/jm020078l.

Abstract

Azacycloalkane turn mimics 6-9 were used to explore the relationship between conformation and biological activity of peptide ligands to the opioid receptor-like (ORL1) receptor. Three azabicyclo[x.y.0]alkane amino acids and a 5-tBuPro type VI beta-turn mimic were introduced into peptides 10-13 by solid-phase synthesis on MBHA resin. Biological examination of peptides 10-13 showed two new antagonists (10 and 12) exhibiting increased selectivity for the ORL1 receptor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acids / chemical synthesis*
  • Amino Acids / chemistry
  • Amino Acids / pharmacology
  • Animals
  • Aza Compounds / chemical synthesis*
  • Aza Compounds / chemistry
  • Aza Compounds / pharmacology
  • CHO Cells
  • COS Cells
  • Cricetinae
  • Guanosine 5'-O-(3-Thiotriphosphate) / metabolism
  • Ligands
  • Narcotic Antagonists*
  • Nociceptin Receptor
  • Peptides / chemical synthesis*
  • Peptides / chemistry
  • Peptides / pharmacology
  • Protein Structure, Secondary
  • Radioligand Assay
  • Receptors, Opioid / agonists
  • Structure-Activity Relationship

Substances

  • Amino Acids
  • Aza Compounds
  • Ligands
  • Narcotic Antagonists
  • Peptides
  • Receptors, Opioid
  • Guanosine 5'-O-(3-Thiotriphosphate)
  • Nociceptin Receptor