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

Authors

Miao Hu, Zhejiang University
Marc Giulianotti, Torrey Pines Institute for Molecular Studies
Jay P. McLaughlin, Torrey Pines Institute for Molecular Studies
Jiaan Shao, Zhejiang University
Ginamarie Debevec, Zhejiang University
Laura E. Maida, Torrey Pines Institute for Molecular Studies
Phaedra Geer, Torrey Pines Institute for Molecular Studies
Margaret Cazares, Torrey Pines Institute for Molecular Studies
Jaime Misler, Torrey Pines Institute for Molecular Studies
Ling Li, Torrey Pines Institute for Molecular Studies
Colette T. Dooley, Torrey Pines Institute for Molecular Studies
Michelle L. Ganno, Torrey Pines Institute for Molecular Studies
Shainnel O. Eans Torrey Pines Institute for Molecular Studies
Elisa Mizrachi, Torrey Pines Institute for Molecular Studies
Radleigh Santos, Torrey Pines Institute for Molecular StudiesFollow
Austin B. Yongye, Torrey Pines Institute for Molecular Studies
Richard A. Houghten, Torrey Pines Institute for Molecular Studies
Yongping Yu, Zhejiang University; Torrey Pines Institute for Molecular Studies

Document Type

Article

Publication Date

3-6-2015

Publication Title

European Journal of Medicinal Chemistry

Keywords

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

ISSN

0223-5234

Volume

92

First Page

270

Last Page

281

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 26produced 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 antinociceptivetolerance. This novel class of peptides adds to the potentially therapeutically relevant collection of previously reported EM analogues.

Comments

Copyright © 2014 Published by Elsevier Masson SAS

NSUWorks Citation

Hu, Miao; Giulianotti, Marc; McLaughlin, Jay P.; Shao, Jiaan; Debevec, Ginamarie; Maida, Laura E.; Geer, Phaedra; Cazares, Margaret; Misler, Jaime; Li, Ling; Dooley, Colette T.; Ganno, Michelle L.; Eans, Shainnel O. Torrey Pines Institute for Molecular Studies; Mizrachi, Elisa; Santos, Radleigh; Yongye, Austin B.; Houghten, Richard A.; and Yu, Yongping, "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" (2015). Mathematics Faculty Articles. 235.
https://nsuworks.nova.edu/math_facarticles/235

DOI

10.1016/j.ejmech.2014.12.049