RT Journal Article SR Electronic T1 Antinociceptive Structure-Activity Studies with Enkephalin-Based Opioid Glycopeptides JF Journal of Pharmacology and Experimental Therapeutics JO J Pharmacol Exp Ther FD American Society for Pharmacology and Experimental Therapeutics SP 290 OP 297 DO 10.1124/jpet.104.069393 VO 311 IS 1 A1 Nura O. Elmagbari A1 Richard D. Egleton A1 Michael M. Palian A1 John J. Lowery A1 Wendi R. Schmid A1 Peg Davis A1 Edita Navratilova A1 Muthu Dhanasekaran A1 Charles M. Keyari A1 Henry I. Yamamura A1 Frank Porreca A1 Victor J. Hruby A1 Robin Polt A1 Edward J. Bilsky YR 2004 UL http://jpet.aspetjournals.org/content/311/1/290.abstract AB Development of opioid peptides as therapeutic agents has historically been limited due to pharmacokinetic issues including stability and blood-brain barrier (BBB) permeability. Glycosylation of opioid peptides can increase peptide serum stability and BBB penetration. To further define the requirements for optimizing in vivo antinociceptive potency following intravenous administration, we synthesized a series of enkephalin-based glycopeptides using solid phase 9-fluorenylmethyloxy carbamate methods. The compounds differed in the sixth and subsequent amino acid residues (Ser or Thr) and in the attached carbohydrate moiety. In vitro binding and functional smooth muscle bioassays indicated that the addition of mono- or disaccharides did not significantly affect the opioid receptor affinity or agonist activity of the glycopeptides compared with their unglycosylated parent peptides. All of the glycopeptides tested produced potent antinociceptive effects in male ICR mice following intracerebroventricular injection in the 55°C tail-flick test. The calculated A50 values for the Ser/Thr and monosaccharide combinations were all very similar with values ranging from 0.02 to 0.09 nmol. Selected compounds were administered to mice intravenously and tested for antinociception to indirectly assess serum stability and BBB penetration. All compounds tested produced full antinociceptive effects with calculated A 50 values ranging from 2.2 to 46.4 μmol/kg with the disaccharides having potencies that equaled or exceeded that of morphine on a micromoles per kilogram basis. Substitution of a trisaccharide or bis- and tris-monosaccharides resulted in a decrease in antinociceptive potency. These results provide additional support for the utility of glycosylation to increase central nervous system bioavailability of small peptides and compliment our ongoing stability and blood-brain barrier penetration studies. The American Society for Pharmacology and Experimental Therapeutics