From the potent and selective mu opioid receptor agonist H-Dmt-d-Arg-Phe-Lys-NH(2) to the potent delta antagonist H-Dmt-Tic-Phe-Lys(Z)-OH

J Med Chem. 2005 Aug 25;48(17):5608-11. doi: 10.1021/jm0504959.

Abstract

H-Dmt-d-Arg-Phe-Lys-NH(2) ([Dmt(1)]DALDA) binds with high affinity and selectivity to the mu opioid receptor and is a potent and long-acting analgesic. Substitution of d-Arg in position 2 with Tic and masking of the lysine amine side chain by Z protection and of the C-terminal carboxylic function instead of the amide function transform a potent and selective mu agonist into a potent and selective delta antagonist H-Dmt-Tic-Phe-Lys(Z)-OH. Such a delta antagonist could be used as a pharmacological tool.

MeSH terms

  • Animals
  • Binding, Competitive
  • Guinea Pigs
  • Ileum / drug effects
  • Ileum / physiology
  • In Vitro Techniques
  • Male
  • Mice
  • Muscle Contraction / drug effects
  • Muscle, Smooth / drug effects
  • Muscle, Smooth / physiology
  • Oligopeptides / chemical synthesis*
  • Oligopeptides / chemistry*
  • Oligopeptides / pharmacology
  • Rats
  • Receptors, Opioid, delta / antagonists & inhibitors*
  • Receptors, Opioid, mu / agonists*
  • Synaptosomes / metabolism
  • Vas Deferens / drug effects
  • Vas Deferens / physiology

Substances

  • 2',6'-dimethyltyrosyl-1,2,3,4-tetrahydroisoquinolinecarbonyl-phenylalanyl-(N(epsilon)-benzyloxycarbonyl)lysine
  • 2',6'-dimethyltyrosyl-arginyl-phenylalanyl-lysinamide
  • Oligopeptides
  • Receptors, Opioid, delta
  • Receptors, Opioid, mu