Synthesis and biological evaluations of novel endomorphin analogues containing α-hydroxy-β-phenylalanine (AHPBA) displaying mixed μ/δ opioid receptor agonist and δ opioid receptor antagonist activities

Eur J Med Chem. 2015 Mar 6:92:270-81. doi: 10.1016/j.ejmech.2014.12.049. Epub 2014 Dec 29.

Abstract

A novel series of endomorphin-1 (EM-1) and endomorphin-2 (EM-2) analogues was synthesized, incorporating chiral α-hydroxy-β-phenylalanine (AHPBA), and/or Dmt(1)-Tic(2) at different positions. Pharmacological activity and metabolic stability of the series was assessed. Consistent with earlier studies of β-amino acid substitution into endomorphins, multiple analogues incorporation AHPBA displayed high affinity for μ and δ opioid receptors (MOR and DOR, respectively) in radioligand competition binding assays, and an increased stability in rat brain membrane homogenates, notably Dmt-Tic-(2R,3S)AHPBA-Phe-NH2 (compound 26). Intracerebroventricular (i.c.v.) administration of 26 produced antinociception (ED50 value (and 95% confidence interval) = 1.98 (0.79-4.15) nmol, i.c.v.) in the mouse 55 °C warm-water tail-withdrawal assay, equivalent to morphine (2.35 (1.13-5.03) nmol, i.c.v.), but demonstrated DOR-selective antagonism in addition to non-selective opioid agonism. The antinociception of 26 was without locomotor activity or acute antinociceptive tolerance. This novel class of peptides adds to the potentially therapeutically relevant collection of previously reported EM analogues.

Keywords: Half-lives; MOR agonist/DOR agonist; MOR agonist/DOR antagonist; Opioid receptors; α-Hydroxy-β-phenylalanine.

Publication types

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

MeSH terms

  • Animals
  • CHO Cells
  • Cricetulus
  • Dihydroxyphenylalanine / analogs & derivatives*
  • Dihydroxyphenylalanine / chemistry*
  • Dose-Response Relationship, Drug
  • HEK293 Cells
  • Humans
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Molecular Conformation
  • Oligopeptides / chemical synthesis*
  • Oligopeptides / chemistry
  • Oligopeptides / pharmacology*
  • Rats
  • Receptors, Opioid, delta / agonists*
  • Receptors, Opioid, delta / antagonists & inhibitors*
  • Receptors, Opioid, mu / agonists*
  • Structure-Activity Relationship

Substances

  • Oligopeptides
  • Receptors, Opioid, delta
  • Receptors, Opioid, mu
  • endomorphin 1
  • endomorphin 2
  • Dihydroxyphenylalanine