US EPA

7449724 

Journal Article 

Antinociceptive structure-activity studies with enkephalin-based opioid glycopeptides 

Elmagbari, NO; Egleton, RD; Palian, MM; Lowery, JJ; Schmid, WR; Davis, P; Navratilova, E; Dhanasekaran, M; Keyari, CM; Yamamura, HI; Porreca, F; Hruby, VJ; Polt, R; Bilsky, EJ 

2004 

Yes 

Journal of Pharmacology and Experimental Therapeutics
ISSN: 0022-3565
EISSN: 1521-0103 

311 

1 

290-297 

English 

15166257 

10.1124/jpet.104.069393 

WOS:000223896100034 

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 degrees C tail-flick test. The calculated A(50) 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 micromol/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. 

9 fluorenylmethyloxycarbamate; carbamic acid derivative; enkephalin derivative; opiate peptide; unclassified drug; amino acid sequence; animal experiment; animal tissue; antinociception; article; binding affinity; bioassay; blood brain barrier; controlled study; drug activity; drug binding; drug effect; drug penetration; drug receptor binding; drug stability; drug structure; drug synthesis; glycosylation; in vitro study; in vivo study; male; membrane permeability; mouse; nonhuman; priority journal; smooth muscle; structure activity relation; tail flick test; Analgesics; Animals; Disease Models, Animal; Enkephalins; Glycopeptides; Male; Mice; Mice, Inbred ICR; Opioid Peptides; Pain; Pain Measurement; Structure-Activity Relationship