Opioid Glycopeptide Analgesics Derived from Endogenous Enkephalins and Endorphins

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.

Structural Requirements for CNS Active Opioid Glycopeptides

“…A possible reason is that the increased hydrophilicity of the disaccharide shifts the residency of glycopeptide 11L into the aqueous compartment, resulting in faster elimination. 9,29 In summary, we suggest that a flexible linker such as GABA and a helical address segment enhances delivery of the opioid message to neurons within the CNS. Opioid selectivity is determined mainly by the identity of the message after icv administration, but the address segment and linker become more important for delivery after peripheral iv administration.…”

In Vitro Membrane Permeation Studies and in Vivo Antinociception of Glycosylated Dmt1-DALDA Analogues

“…In the opioid peptide field, glycosylation has been used as a method to increase enzymatic stability 2,3 and to improve the analgesic profile of several opioid peptides. 4 …”

“…7,8 The in vitro pharmacological evaluation of these peptides revealed that bioactivity was dependent on the linker type, the identity of the sugar unit, and the position of conjugation. 4 With respect to the anchorage site and on the basis of previous research, two different conjugation positions were considered in this work. In the past, numerous glycosylations have been carried out on the enkephalin sequences.…”

“…1–9 When the glycosylated residue was introduced at the C-terminus (e.g., 2 in Figure 1) of the sequence, high affinity for the μ opioid receptor was maintained. 4 In contrast, when the sugar was attached in the proximity of the N-terminus in an enkephalin-based sequence, a substantial loss in potency was apparent. 9 In addition, early SAR studies prematurely concluded that structural modifications at the phenolic function of aromatic amino acids in position 1 of opioid peptides would be detrimental for analgesic activity.…”

“…In the case of compounds 4 and 5 , the conjugated galactose and glucose subunits were found to be compatible with MOR activity ($K_{\mathrm{i}}^{\mu }$, 0.222 and 0.203 nM, and GPI IC 50 , 0.66 and 1.46 nM, respectively). However, upon replacement of the aminoalkyl side chain of Lys 4 in 1 with a triazolyl-Glu/Gal functionality, the μ/δ receptor binding selectivity ratio was dramatically lowered ( K i μ/δ ratio 11 400 ( 1 ) → 70 ( 4 ) and 58 ( 5 )). The high $K_{\mathrm{i}}^{\delta }$ value of 1 (2100 nM) shifted to 15.6 and 11.9 nM for 4 and 5 , respectively.…”