Novel glycosylated endomorphin-2 analog produces potent centrally-mediated antinociception in mice after peripheral administration.
We report the synthesis and pharmacological characterization of a novel glycosylated analog of a potent and selective endogenous μ-opioid receptor (MOP) agonist, endomorphin-2 (Tyr-Pro-Phe-Phe-NH2, EM-2), obtained by the introduction in position 3 of the tyrosine residue possessing the glucose moiety attached to the phenolic function via a β-glycosidic bond. The improved blood-brain barrier permeability and enhanced antinociceptive effect of the novel glycosylated analog suggest that it may be a promising template for design of potent analgesics. Furthermore, the described methodology may be useful for increasing the bioavailability and delivery of opioid peptides to the CNS.
Department of Biomolecular Chemistry, Faculty of Medicine, Medical University of Lodz, Mazowiecka 6/8, 92-215 Lodz, Poland; Department of Gastroenterological Surgery, Tenth People's Hospital of Shanghai, School of Medicine, Tongji University, Shanghai, China. Electronic address: jakub.fichna@umed.lodz.pl.
Jakub
J
Fichna
Marzena
M
Mazur
Daria
D
Grzywacz
Wojciech
W
Kamysz
Renata
R
Perlikowska
Justyna
J
Piekielna
Marta
M
Sobczak
Maciej
M
Sałaga
Geza
G
Toth
Anna
A
Janecka
Chunqiu
C
Chen
Jacek
J
Olczak
D000595:Amino Acid Sequence; D000700:Analgesics / Q000737:chemistry* / Q000494:pharmacology; D000818:Animals; D001812:Blood-Brain Barrier / Q000378:metabolism; D006031:Glycosylation; D007275:Injections, Intravenous; D051379:Mice; D009842:Oligopeptides / Q000737:chemistry* / Q000494:pharmacology*; D010147:Pain Measurement / Q000187:drug effects; D010539:Permeability / Q000187:drug effects; D017450:Receptors, Opioid, mu / Q000819:agonists* / Q000378:metabolism
D000700:Analgesics; D009842:Oligopeptides; D017450:Receptors, Opioid, mu; C105294:endomorphin 2
1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate; 2-chloro-4,6-bis[3-(perfluorohexyl)propyloxy]-1,3,5-triazine; AgOTf; Antinociception; BBB; CDMT; CNS; DMF; EM-2; Endomorphin-2; Fmoc; GPI assay; HATU; HR-ESI-MS; MOP; N-(9-fluorenylmethyloxycarbonyl); NALME; O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate; Peripheral administration; RP HPLC; TBTU; TFA; blood–brain barrier; central nervous system; dimethylformamide; endomorphin-2; guinea pig ileum assay; high-resolution electrospray ionization mass spectrometry; intravenous; iv; naloxone methiodide; reversed-phase high-performance liquid chromatography; silver triflate; trifluoroacetic acid; μ-opioid receptor; μ-opioid receptor (MOP)