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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 :
Colette T. Dooley
Richard A. Houghten
Margaret E. Cazares
Jiaan Shao
Miao Hu
Austin B. Yongye
Radleigh G. Santos
Elisa Mizrachi
Jay P. McLaughlin
Marc A. Giulianotti
Ginamarie Debevec
Michelle L. Ganno
Shainnel O. Eans
Jaime A. Misler
Ling Li
Laura E. Maida
Phaedra Geer
Yongping Yu
Source :
European Journal of Medicinal Chemistry. 92:270-281
Publication Year :
2015
Publisher :
Elsevier BV, 2015.

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.

Details

ISSN :
02235234
Volume :
92
Database :
OpenAIRE
Journal :
European Journal of Medicinal Chemistry
Accession number :
edsair.doi.dedup.....400a8fd538a53b0388e238eacd7ddb7a
Full Text :
https://doi.org/10.1016/j.ejmech.2014.12.049