Systemic analgesic activity and delta-opioid selectivity in [2,6-dimethyl-Tyr1,D-Pen2,D-Pen5]enkephalin

J Med Chem. 1992 Feb 21;35(4):684-7. doi: 10.1021/jm00082a008.


The cyclic peptide [2,6-dimethyl-Tyr1,D-Pen2,D-Pen5]enkephalin (2) was synthesized by solid-phase techniques and contains the optically pure unnatural amino acid 2,6-dimethyltyrosine (DMT) as a replacement for the Tyr1 residue of [D-Pen2,D-Pen5]enkephalin (DPDPE, 1). This structural modification resulted in a 10-fold increase in the potency of 2 at the delta opioid receptor and a 35-fold increase in potency at the mu receptor while substantial delta receptor selectivity was maintained. In addition, 2 was 86-fold more effective than 1 at inhibiting electrically stimulated contractions of the mouse vas deferens. In the hot plate test, 2 was 7-fold more potent than 1 after intracerebroventricular administration in the mouse. While 1 was inactive following systemic administration of doses as high as 30 mg/kg, subcutaneous administration of 2 significantly inhibited writhing with an ED50 of 2.6 mg/kg. These results demonstrate that the potency and systemic activity of DPDPE are significantly increased by replacement of Tyr1 with DMT.

MeSH terms

  • Analgesia*
  • Analgesics / chemical synthesis
  • Analgesics / metabolism
  • Analgesics / pharmacology*
  • Animals
  • Brain / metabolism
  • Cell Membrane / metabolism
  • Electric Stimulation
  • Enkephalins / chemical synthesis
  • Enkephalins / metabolism
  • Enkephalins / pharmacology*
  • Male
  • Mice
  • Mice, Inbred ICR
  • Muscle Contraction / drug effects
  • Pain Measurement
  • Receptors, Opioid / physiology*
  • Receptors, Opioid, delta
  • Receptors, Opioid, mu
  • Structure-Activity Relationship
  • Vas Deferens / drug effects
  • Vas Deferens / physiology


  • Analgesics
  • Enkephalins
  • Receptors, Opioid
  • Receptors, Opioid, delta
  • Receptors, Opioid, mu
  • enkephalin, 2,6-dimethyl-Tyr(1)-Pen(2,5)-