title: Bifunctional [2',6'-dimethyl-L-tyrosine1]endomorphin-2 analogues substituted at position 3 with alkylated phenylalanine derivatives yield potent mixed mu-agonist/delta-antagonist and dual mu-agonist/delta-agonist opioid ligands.
abstract: Endomorphin-2 (H-Tyr-Pro-Phe-Phe-NH2) and [Dmt1]EM-2 (Dmt = 2',6'-dimethyl-l-tyrosine) analogues, containing alkylated Phe3 derivatives, 2'-monomethyl (2, 2'), 3',5'- and 2',6'-dimethyl (3, 3', and 4', respectively), 2',4',6'-trimethyl (6, 6'), 2'-ethyl-6'-methyl (7, 7'), and 2'-isopropyl-6'-methyl (8, 8') groups or Dmt (5, 5'), had the following characteristics: (i) [Xaa3]EM-2 analogues exhibited improved mu- and delta-opioid receptor affinities. The latter, however, were inconsequential (Kidelta = 491-3451 nM). (ii) [Dmt1,Xaa3]EM-2 analogues enhanced mu- and delta-opioid receptor affinities (Kimu = 0.069-0.32 nM; Kidelta = 1.83-99.8 nM) without kappa-opioid receptor interaction. (iii) There were elevated mu-bioactivity (IC50 = 0.12-14.4 nM) and abolished delta-agonism (IC50 > 10 muM in 2', 3', 4', 5', 6'), although 4' and 6' demonstrated a potent mixed mu-agonism/delta-antagonism (for 4', IC50mu = 0.12 and pA2 = 8.15; for 6', IC50mu = 0.21 nM and pA2 = 9.05) and 7' was a dual mu-agonist/delta-agonist (IC50mu = 0.17 nM; IC50delta = 0.51 nM).
authors.affiliation: The Graduate School of Food and Medicinal Sciences and Faculty of Pharmaceutical Sciences, Kobe Gakuin University, Nishi-ku, Kobe 651-2180, Japan.
authors.forename: Tingyou
authors.initials: T
authors.lastname: Li
authors.forename: Kimitaka
authors.initials: K
authors.lastname: Shiotani
authors.forename: Anna
authors.initials: A
authors.lastname: Miyazaki
authors.forename: Yuko
authors.initials: Y
authors.lastname: Tsuda
authors.forename: Akihiro
authors.initials: A
authors.lastname: Ambo
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Sasaki
authors.forename: Yunden
authors.initials: Y
authors.lastname: Jinsmaa
authors.forename: Ewa
authors.initials: E
authors.lastname: Marczak
authors.forename: Sharon D
authors.initials: SD
authors.lastname: Bryant
authors.forename: Lawrence H
authors.initials: LH
authors.lastname: Lazarus
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Okada
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000378:metabolism; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008024:Ligands; D008297:Male; D051379:Mice; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects / Q000294:innervation / Q000502:physiology; D009197:Myenteric Plexus / Q000502:physiology; D009469:Neuromuscular Junction / Q000187:drug effects / Q000502:physiology; D009842:Oligopeptides / Q000138:chemical synthesis* / Q000494:pharmacology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D017465:Receptors, Opioid, delta / Q000819:agonists* / Q000037:antagonists & inhibitors*; D017450:Receptors, Opioid, mu / Q000819:agonists*; D013329:Structure-Activity Relationship; D013574:Synaptosomes / Q000378:metabolism; D014443:Tyrosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology; D014649:Vas Deferens / Q000187:drug effects / Q000502:physiology
chemical_list: D008024:Ligands; D009842:Oligopeptides; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; C105294:endomorphin 2; D014443:Tyrosine