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Glycosylation Improves the Central Effects of DAMGO
Author(s) -
Lowery John J.,
Yeomans Larisa,
Keyari Charles M.,
Davis Peg,
Porreca Frank,
Knapp Brian I.,
Bidlack Jean M.,
Bilsky Edward J.,
Polt Robin
Publication year - 2007
Publication title -
chemical biology and drug design
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.59
H-Index - 77
eISSN - 1747-0285
pISSN - 1747-0277
DOI - 10.1111/j.1747-0285.2007.00462.x
Subject(s) - chemistry , damgo , amide , solubility , agonist , glycosylation , serine , polar surface area , stereochemistry , receptor , biochemistry , molecule , organic chemistry , opioid receptor , phosphorylation
A series of μ ‐agonist DAMGO analogs were synthesized and pharmacologically characterized to test the ‘biousian’ hypothesis of membrane hopping. DAMGO was altered by incorporating moieties of increasing water solubility into the C‐terminus via carboxamide and simple glycoside additions. The hydrophilic C‐terminal moieties were varied from glycinol in DAMGO ( 1 ) to l ‐serine amide ( 2 ), l ‐serine amide β ‐ d ‐xyloside ( 3 ), l ‐serine amide β ‐ d ‐glucoside ( 4 ), and finally to l ‐serine amide β ‐lactoside ( 5 ). Opioid binding and mouse tail‐flick studies were performed. Antinociceptive potency (intravenous) increased, passing through a maximum (A 50 ≈ 0.2 μ mol/kg) for 2 and 3 as membrane affinity versus water solubility became optimal, and dropped off (A 50 ≈ 1.0 μ mol/kg) for 4 and 5 as water solubility dominated molecular behavior. Intravenous A 50 values were plotted versus hydrodynamic values (glucose units, g.u.) for the glycoside moieties, or the hydrophilic/hydrophobic Connolly surface areas (A 50 versus e −Awater/Alipid ), and provided either a V‐shaped or a U‐shaped curve, as predicted by the ‘biousian’ hypothesis. The μ ‐selective receptor profile was maintained ( K i ’s = 0.66–1.3 n m ) upon modifications at the C‐terminus. The optimal ‘degree of glycosylation’ for the DAMGO peptide message appears to be between 1.25 and 1.75 g.u. (hydrodynamic g.u.), or 0.75 and 0.90 in terms of the surface‐derived amphipathicity values.