TY - JOUR
T1 - 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
AU - Hu, Miao
AU - Giulianotti, Marc A.
AU - McLaughlin, Jay P.
AU - Shao, Jiaan
AU - Debevec, Ginamarie
AU - Maida, Laura E.
AU - Geer, Phaedra
AU - Cazares, Margaret
AU - Misler, Jaime
AU - Li, Ling
AU - Dooley, Colette
AU - Ganno, Michelle L.
AU - Eans, Shainnel O.
AU - Mizrachi, Elisa
AU - Santos, Radleigh G.
AU - Yongye, Austin B.
AU - Houghten, Richard A.
AU - Yu, Yongping
N1 - Publisher Copyright:
© 2014 Published by Elsevier Masson SAS.
PY - 2015/1/27
Y1 - 2015/1/27
N2 - 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.
AB - 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.
KW - Half-lives
KW - MOR agonist/DOR agonist
KW - MOR agonist/DOR antagonist
KW - Opioid receptors
KW - α-Hydroxy-β-phenylalanine
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U2 - 10.1016/j.ejmech.2014.12.049
DO - 10.1016/j.ejmech.2014.12.049
M3 - Article
C2 - 25559207
AN - SCOPUS:84920142605
SN - 0223-5234
VL - 92
SP - 270
EP - 281
JO - European Journal of Medicinal Chemistry
JF - European Journal of Medicinal Chemistry
ER -