Novel glycosylated endomorphin-2 analog produces potent centrally-mediated antinociception in mice after peripheral administration

Abstract

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.

Keywords: 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).