[Nalpha-benzylTyr1,cyclo(D-Asp5,Dap8)]- dynorphin A-(1-11)NH2 cyclized in the "address" domain is a novel kappa-opioid receptor antagonist

J Med Chem. 2005 Jul 14;48(14):4500-3. doi: 10.1021/jm050105i.

Abstract

The cyclic dynorphin A analogue [N(alpha)-benzylTyr(1),cyclo(D-Asp(5),Dap(8))]dynorphin A-(1-11)NH(2) (Dap = 2,3-diaminopropionic acid) exhibits nanomolar affinity (30 nM) and high selectivity (K(i) ratio (kappa/mu/delta) = 1/194/330) for kappa-opioid receptors. This analogue antagonizes dynorphin A-(1-13)NH(2) at kappa-opioid receptors in the adenylyl cyclase assay (K(B) = 84 nM). This is the first dynorphin A-based antagonist with modifications in the C-terminal "address" domain that alter efficacy and thus represents a novel selective kappa-opioid receptor antagonist.

Publication types

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

MeSH terms

  • Adenylyl Cyclases / biosynthesis
  • Animals
  • CHO Cells
  • Cricetinae
  • Cricetulus
  • Cyclization
  • Dynorphins / chemical synthesis*
  • Dynorphins / chemistry
  • Dynorphins / pharmacology
  • Molecular Conformation
  • Peptide Fragments / chemical synthesis*
  • Peptide Fragments / chemistry
  • Peptide Fragments / pharmacology
  • Protein Structure, Tertiary
  • Radioligand Assay
  • Receptors, Opioid, kappa / antagonists & inhibitors*
  • Structure-Activity Relationship

Substances

  • Peptide Fragments
  • Receptors, Opioid, kappa
  • dynorphin A-(1-11)-NH2, Nalpha-benzylTyr(1)-cyclo(Asp(5)-Dap(8))-
  • Dynorphins
  • Adenylyl Cyclases