Design and synthesis of highly potent and selective cyclic dynorphin A analogues

J Med Chem. 1990 Jul;33(7):1874-9. doi: 10.1021/jm00169a007.


We have designed and synthesized several cyclic disulfide-containing peptide analogues of dynorphin A (Dyn A) which are conformationally constrained in the putative "address" segment of the opioid ligand. Several of these Dyn A analogues exhibit unexpected selectivities for the kappa and mu opioid receptors(s) of the central vs peripheral nervous systems. Thus, incorporation of conformational constraint in the putative "address" segment of Dyn A analogues has resulted in the kappa/mu opioid receptor ligands [Cys5,Cys11]Dyn A1-11-NH2 (1) and [Cys5,Cys11,D-Ala8]Dyn A1-11-NH2 (2), which possess high kappa and mu opioid receptor affinities centrally (guinea pig brain, GPB), but only weak activity at peripheral kappa and mu opioid receptors (guinea pig ileum, GPI). On the other hand, [Cys8,Cys13]Dyn A1-13-NH2 and [D-Cys8,D-Cys13]Dyn A1-13-NH2 (5) display high kappa potencies and selectivities at the peripheral (GPI) but not at the central (GPB) kappa opioid receptor. The lack of correlation between the pharmacological profiles observed in smooth muscle and in the brain binding assays suggests the existence of different subtypes of the kappa and mu opioid receptors in the brain and peripheral nervous systems.

Publication types

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

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Brain / metabolism
  • Drug Design
  • Dynorphins / analogs & derivatives*
  • Dynorphins / chemical synthesis*
  • Dynorphins / pharmacology
  • Electric Stimulation
  • Guinea Pigs
  • Ileum / physiology
  • In Vitro Techniques
  • Indicators and Reagents
  • Male
  • Molecular Sequence Data
  • Muscle Contraction / drug effects*
  • Muscle, Smooth / drug effects
  • Muscle, Smooth / physiology*
  • Myenteric Plexus / drug effects
  • Myenteric Plexus / physiology
  • Peptides, Cyclic / chemical synthesis*
  • Peptides, Cyclic / pharmacology
  • Protein Conformation
  • Receptors, Opioid / drug effects*
  • Receptors, Opioid / metabolism
  • Spectrum Analysis
  • Structure-Activity Relationship


  • Indicators and Reagents
  • Peptides, Cyclic
  • Receptors, Opioid
  • Dynorphins