2. Academic Validation
  3. 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

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.
Miao Hu 1,  Marc A Giulianotti 2,  Jay P McLaughlin 2,  Jiaan Shao 1,  Ginamarie Debevec 2,  Laura E Maida 2,  Phaedra Geer 2,  Margaret Cazares 2,  Jaime Misler 2,  Ling Li 2,  Colette Dooley 2,  Michelle L Ganno 2,  Shainnel O Eans 2,  Elisa Mizrachi 2,  Radleigh G Santos 2,  Austin B Yongye 2,  Richard A Houghten 3,  Yongping Yu 4
Affiliations

Affiliations

  • 1 Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, PR China.
  • 2 Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, Port St. Lucie, FL 34987, USA.
  • 3 Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, Port St. Lucie, FL 34987, USA. Electronic address: [email protected].
  • 4 Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, PR China; Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, Port St. Lucie, FL 34987, USA. Electronic address: [email protected].
PMID: 25559207 DOI: 10.1016/j.ejmech.2014.12.049
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.

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