Structural Requirements for CNS Active Opioid Glycopeptides

Glycopeptides
related to β-endorphin penetrate the blood–brain
barrier (BBB) of mice to produce antinociception. Two series of glycopeptides
were assessed for opioid receptor binding affinity. Attempts to alter
the mu-selectivity of [d-Ala2,N-MePhe4,Gly-ol5]­enkephalin (DAMGO)-related
glycopeptides by altering the charged residues of the amphipathic
helical address were unsuccessful. A series of pan-agonists was evaluated
for antinociceptive activity (55 °C tail flick) in mice. A flexible
linker was required to maintain antinociceptive activity. Circular
dichroism (CD) in H2O, trifluoroethanol (TFE), and SDS
micelles confirmed the importance of the amphipathic helices (11s → 11sG → 11) for
antinociception. The glycosylated analogues showed only nascent helices
and random coil conformations in H2O. Chemical shift indices
(CSI) and nuclear Overhauser effects (NOE) with 600 MHz NMR and CD
confirmed helical structures in micelles, which were rationalized
by molecular dynamics calculations. Antinociceptive studies with mice
confirm that these glycosylated endorphin analogues are potential
drug candidates that penetrate the BBB to produce potent central effects.