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Review
. 2012 Feb;4(2):205-26.
doi: 10.4155/fmc.11.195.

Opioid glycopeptide analgesics derived from endogenous enkephalins and endorphins

Yingxue Li  1 , Mark R Lefever, Dhanasekaran Muthu, Jean M Bidlack, Edward J Bilsky, Robin Polt
Affiliations
Review

Opioid glycopeptide analgesics derived from endogenous enkephalins and endorphins

Yingxue Li et al. Future Med Chem. 2012 Feb.

Abstract

Over the past two decades, potent and selective analgesics have been developed from endogenous opioid peptides. Glycosylation provides an important means of modulating interaction with biological membranes, which greatly affects the pharmacodynamics and pharmacokinetics of the resulting glycopeptide analogues. Furthermore, manipulation of the membrane affinity allows penetration of cellular barriers that block efficient drug distribution, including the blood-brain barrier. Extremely potent and selective opiate agonists have been developed from endogenous peptides, some of which show great promise as drug candidates.

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Figures

Figure 1
Figure 1. Opioid receptors
The μ-opioid receptor G-protein-coupled receptor derived from bovine rhodopsin by homology modeling [12].
Figure 2
Figure 2. Membrane hopping
Endogenous opioids associate with the membranes (kon >> koff) and bind to one or more of the opioid receptors via a membrane-bound conformation (Fisher's lock and key). Studies show that active (folded) conformations are favored in the membrane and inactive (random coil) conformations are favored in the absence of a membrane. Incorporation of glycosides, represented by the 270° arc, can shift the kon/koff equilibrium to facilitate ‘membrane hopping’.
Figure 3
Figure 3. The neurovascular unit
The neurovascular unit forms the blood–brain barrier that prevents the passage of most peptides and other polar substances from the capillaries into the brain. AE: Astrocyte endprocess; BL: Basolateral membrane; EC: Endothelial cell; NU: Neutrophil; P: Pericyte; TJ: Tight junction.
Figure 4
Figure 4. Minimally competent Lewis acids as glycosidation promotors
Lewis acids such as InBr3 can dissociate (lower pathway) from the displaced acetate to form acetic acid and regenerate the Lewis acid catalyst. Stronger Lewis acids remain associated with the acetate (upper pathway) to produce a Brønsted acid and, generally, require a full equivalent of the Lewis acid.
Figure 5
Figure 5. Glycopeptide assembly
MBHA-functionalized Rink polystyrene resin was used to provide the C-terminal amides upon cleavage after classical Fmoc construction of the glycopeptides. Treatment with hydrazine hydrate (H2NNH2•H2O) in methanol (CH3OH) was required to remove the acetates from the glycoside moiety prior to cleavage from the Rink resin. A Boc-protected amino acid may be used for the final amino acid (O-tBu-Tyr), which is cleaved with the TFA cocktail.
Figure 6
Figure 6. Antinociception studies indicate a U-shaped or V-shaped curve when the A50 potency values are correlated with predicted amphipathicity
The hydrodynamic values (glucose units) or Connolly-derived amphipathicity values are plotted along the X-axes, and A50 values derived from mouse intravenous tail-flick data are plotted on the Y-axis. Both analyses produce a U-shape or V-shape, as predicted by the biousian hypothesis [84]. The amphipathicity values were calculated using the formula A = e–Awater/Alipid, where Awater = the Connolly surface area of the hydrophilic moiety (Å2) and Alipid = the Connolly surface area of the rest of the lipophilic peptide message segment YaG(N-MeF).
Figure 7
Figure 7. Representations of the amphipathic helical region in β-endorphin
(A) Human β-endorphin [–28] represented both as an α-helical net projection (left) and as a π-helical net projection (right) [90]. The lipophilic (hydrophobic) residues are circled. (B) Human β-endorphin [–30] represented as an axial projection of a π-helix [91].
Figure 8
Figure 8
Micelle-bound structures of glycopeptide analogues determined by NMR related to (A) enkephalins and (B) endorphins [92,93].
Figure 9
Figure 9. Biousian behavior in a helix context
Modulation of amphipathic helix stability should modulate interactions with biological membranes and ‘searching’ for the receptor.
Figure 10
Figure 10. Circular dichroism to measure helicity
Modulation of the amphipathic helix stability can be directly measured by examining the circular dichroism behavior in (A) sodium dodecylsulfate, (B) trifluoroethanol and (C) water, and measuring the elipticity at 222 nm.
Figure 11
Figure 11
Helicity in sodium dodecyl sulfate as a function of peptide address sequence and glycosylation state.
See this image and copyright information in PMC

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