Glycosylation improves the central effects of DAMGO.
A series of mu-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 beta-d-xyloside (3), l-serine amide beta-d-glucoside (4), and finally to l-serine amide beta-lactoside (5). Opioid binding and mouse tail-flick studies were performed. Antinociceptive potency (intravenous) increased, passing through a maximum (A(50) approximately 0.2 micromol/kg) for 2 and 3 as membrane affinity versus water solubility became optimal, and dropped off (A(50) approximately 1.0 micromol/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 mu-selective receptor profile was maintained (K(i)'s = 0.66-1.3 nm) 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.
Lowery
John J
JJ
Department of Pharmacology, University of New England, 11 Hill Beach Rd., Biddeford, Maine 04005, USA.
Yeomans
Larisa
L
Keyari
Charles M
CM
Davis
Peg
P
Porreca
Frank
F
Knapp
Brian I
BI
Bidlack
Jean M
JM
Bilsky
Edward J
EJ
Polt
Robin
R
D000577:Amides / Q000737:chemistry; D000701:Analgesics, Opioid / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)- / Q000378:metabolism / Q000494:pharmacology*; D005947:Glucose / Q000031:analogs & derivatives; D005998:Glycine / Q000031:analogs & derivatives; D006031:Glycosylation; D057927:Hydrophobic and Hydrophilic Interactions; D007276:Injections, Intraventricular; D007785:Lactose / Q000031:analogs & derivatives; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D017450:Receptors, Opioid, mu / Q000187:drug effects* / Q000378:metabolism; D012694:Serine / Q000031:analogs & derivatives; D012995:Solubility; D014867:Water / Q000737:chemistry; D014994:Xylose / Q000031:analogs & derivatives
D000577:Amides; D000701:Analgesics, Opioid; D017450:Receptors, Opioid, mu; D014867:Water; D020875:Enkephalin, Ala(2)-MePhe(4)-Gly(5)-; D012694:Serine; D014994:Xylose; D005947:Glucose; D007785:Lactose; D005998:Glycine