Receptor constants for endomorphin-1 and endomorphin-1-ol indicate differences in efficacy and receptor occupancy

Eur J Pharmacol. 2001 Jun 1;421(1):61-7. doi: 10.1016/s0014-2999(01)01014-7.

Abstract

The opioid properties of endomorphin derivatives containing a C-terminal alcoholic(-ol) function were compared to the parent amidated compounds in isolated organs (longitudinal muscle strip of guinea-pig ileum and mouse vas deferens). Similar data were also generated for the mu-opioid receptor selective agonist synthetic peptide (D-Ala2, MePhe4, Gly5-ol)-enkephalin (DAMGO) and its Gly5-NH2 congener (DAMGA). Endomorphin-1-ol (Tyr-Pro-Trp-Phe-ol) had an IC50 of 80.6 nM in mouse vas deferens and 61.2 nM in guinea-pig ileum; the corresponding values for endomorphin-2-ol (Tyr-Pro-Phe-Phe-ol) were 49.6 and 48.2 nM, for DAMGO 59.8 and 29.2 nM, respectively. As it was indicated by the antagonism by naltrexone, the agonist actions were exerted exclusively at mu-opioid receptors in both organs. The -ol derivatives were slightly (2.3-4.3 times) less potent than the parent amides in the bioassays: all peptides had, apparently, full agonist properties in intact preparations. With the aim of revealing potential partial agonist properties among the investigated peptides, we partially inactivated the mu-opioid receptor pool in mouse vas deferens by 5x10(-7) M beta-funaltrexamine. The calculated receptor constants indicated a "high-affinity, low intrinsic efficacy" profile (i.e. a potential partial agonist property) for endomorphin-1, an intermediate character for endomorpin-1-ol and full agonism for DAMGA and DAMGO. Apparently, a higher receptor fraction remained accessible for endomorphin-1 (42.8%) than for the -ol congener (14.0%), DAMGO (20.2%) and DAMGA (14.1%) after partial inactivation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Analgesics, Opioid / pharmacology
  • Animals
  • Binding, Competitive / drug effects
  • Dose-Response Relationship, Drug
  • Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / metabolism
  • Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / pharmacology
  • Guinea Pigs
  • In Vitro Techniques
  • Male
  • Mice
  • Oligopeptides / chemistry
  • Oligopeptides / metabolism*
  • Oligopeptides / pharmacology
  • Receptors, Opioid, mu / agonists
  • Receptors, Opioid, mu / metabolism*
  • Vas Deferens / drug effects
  • Vas Deferens / metabolism*

Substances

  • Analgesics, Opioid
  • Oligopeptides
  • Receptors, Opioid, mu
  • endomorphin 1
  • Enkephalin, Ala(2)-MePhe(4)-Gly(5)-
  • endomorphin 2