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

Miao Hu, Marc A. Giulianotti, Jay P. McLaughlin, Jiaan Shao, Ginamarie Debevec, Laura E. Maida, Phaedra Geer, Margaret Cazares, Jaime Misler, Ling Li, Colette Dooley, Michelle L. Ganno, Shainnel O. Eans, Elisa Mizrachi, Radleigh G. Santos, Austin B. Yongye, Richard A. Houghten, Yongping Yu

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

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 Dmt1-Tic2 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) Combining double low line 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.

Original languageEnglish (US)
Pages (from-to)270-281
Number of pages12
JournalEuropean Journal of Medicinal Chemistry
Volume92
DOIs
StatePublished - Jan 27 2015
Externally publishedYes

Bibliographical note

Publisher Copyright:
© 2014 Published by Elsevier Masson SAS.

Keywords

  • Half-lives
  • MOR agonist/DOR agonist
  • MOR agonist/DOR antagonist
  • Opioid receptors
  • α-Hydroxy-β-phenylalanine

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