PMID- 25559207 OWN - NLM STAT- MEDLINE DCOM- 20151202 LR - 20170919 IS - 1768-3254 (Electronic) IS - 0223-5234 (Linking) VI - 92 DP - 2015 Mar 6 TI - Synthesis and biological evaluations of novel endomorphin analogues containing alpha-hydroxy-beta-phenylalanine (AHPBA) displaying mixed mu/delta opioid receptor agonist and delta opioid receptor antagonist activities. PG - 270-81 LID - S0223-5234(14)01158-1 [pii] LID - 10.1016/j.ejmech.2014.12.049 [doi] AB - A novel series of endomorphin-1 (EM-1) and endomorphin-2 (EM-2) analogues was synthesized, incorporating chiral alpha-hydroxy-beta-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 beta-amino acid substitution into endomorphins, multiple analogues incorporation AHPBA displayed high affinity for mu and delta 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 degrees 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. CI - Copyright (c) 2014. Published by Elsevier Masson SAS. FAU - Hu, Miao AU - Hu M AD - Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, PR China. FAU - Giulianotti, Marc A AU - Giulianotti MA AD - Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, Port St. Lucie, FL 34987, USA. FAU - McLaughlin, Jay P AU - McLaughlin JP AD - Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, Port St. Lucie, FL 34987, USA. FAU - Shao, Jiaan AU - Shao J AD - Zhejiang Province Key Laboratory of Anti-Cancer Drug Research, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, PR China. FAU - Debevec, Ginamarie AU - Debevec G AD - Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, Port St. Lucie, FL 34987, USA. FAU - Maida, Laura E AU - Maida LE AD - Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, Port St. Lucie, FL 34987, USA. FAU - Geer, Phaedra AU - Geer P AD - Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, Port St. Lucie, FL 34987, USA. FAU - Cazares, Margaret AU - Cazares M AD - Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, Port St. Lucie, FL 34987, USA. FAU - Misler, Jaime AU - Misler J AD - Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, Port St. Lucie, FL 34987, USA. FAU - Li, Ling AU - Li L AD - Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, Port St. Lucie, FL 34987, USA. FAU - Dooley, Colette AU - Dooley C AD - Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, Port St. Lucie, FL 34987, USA. FAU - Ganno, Michelle L AU - Ganno ML AD - Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, Port St. Lucie, FL 34987, USA. FAU - Eans, Shainnel O AU - Eans SO AD - Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, Port St. Lucie, FL 34987, USA. FAU - Mizrachi, Elisa AU - Mizrachi E AD - Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, Port St. Lucie, FL 34987, USA. FAU - Santos, Radleigh G AU - Santos RG AD - Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, Port St. Lucie, FL 34987, USA. FAU - Yongye, Austin B AU - Yongye AB AD - Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, Port St. Lucie, FL 34987, USA. FAU - Houghten, Richard A AU - Houghten RA AD - Torrey Pines Institute for Molecular Studies, 11350 SW Village Parkway, Port St. Lucie, FL 34987, USA. Electronic address: houghten@tpims.org. FAU - Yu, Yongping AU - Yu Y AD - 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: yyu@zju.edu.cn. LA - eng GR - 1R01DA031370/DA/NIDA NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20141229 PL - France TA - Eur J Med Chem JT - European journal of medicinal chemistry JID - 0420510 RN - 0 (Oligopeptides) RN - 0 (Receptors, Opioid, delta) RN - 0 (Receptors, Opioid, mu) RN - 0 (endomorphin 1) RN - 3PH5M0466G (endomorphin 2) RN - 63-84-3 (Dihydroxyphenylalanine) SB - IM MH - Animals MH - CHO Cells MH - Cricetulus MH - Dihydroxyphenylalanine/*analogs & derivatives/*chemistry MH - Dose-Response Relationship, Drug MH - HEK293 Cells MH - Humans MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Mice, Knockout MH - Molecular Conformation MH - Oligopeptides/*chemical synthesis/chemistry/*pharmacology MH - Rats MH - Receptors, Opioid, delta/*agonists/*antagonists & inhibitors MH - Receptors, Opioid, mu/*agonists MH - Structure-Activity Relationship OTO - NOTNLM OT - Half-lives OT - MOR agonist/DOR agonist OT - MOR agonist/DOR antagonist OT - Opioid receptors OT - alpha-Hydroxy-beta-phenylalanine EDAT- 2015/01/07 06:00 MHDA- 2015/12/15 06:00 CRDT- 2015/01/07 06:00 PHST- 2014/06/29 00:00 [received] PHST- 2014/12/28 00:00 [accepted] PHST- 2015/01/07 06:00 [entrez] PHST- 2015/01/07 06:00 [pubmed] PHST- 2015/12/15 06:00 [medline] AID - S0223-5234(14)01158-1 [pii] AID - 10.1016/j.ejmech.2014.12.049 [doi] PST - ppublish SO - Eur J Med Chem. 2015 Mar 6;92:270-81. doi: 10.1016/j.ejmech.2014.12.049. Epub 2014 Dec 29.