Development of a Bioavailable μ Opioid Receptor (MOPr) Agonist, δ Opioid Receptor (DOPr) Antagonist Peptide That Evokes Antinociception without Development of Acute Tolerance

Abstract

We have previously described a cyclic tetrapeptide, 1, that displays μ opioid receptor (MOPr) agonist and δ opioid receptor (DOPr) antagonist activity, a profile associated with a reduced incidence of opioid tolerance and dependence. Like many peptides, 1 has poor bioavailability. We describe here an analogue of 1 with an added C-terminal β-glucosylserine residue, Ser(β-Glc)NH2, a modification that has previously been shown to improve bioavailability of opioid peptides. The resulting peptide, 4, exhibits full antinociceptive efficacy in the mouse warm water tail withdrawal assay after intraperitoneal administration with potency similar to that of morphine. Further, 4 does not give rise to acute tolerance and thus represents a promising lead for the development of opioid analgesics with reduced side effects.

Further Optimization and Evaluation of Bioavailable, Mixed-Efficacy μ-Opioid Receptor (MOR) Agonists/δ-Opioid Receptor (DOR) Antagonists: Balancing MOR and DOR Affinities

“…However, multi-drug regimens may produce pharmacokinetic complications and lead to low patient compliance. 9–11 Thus, we 1–2, 12–14 and others 3–5,15,16 have pursued the development of bifunctional, mixed-efficacy MOR agonist/DOR antagonist ligands. We first reported the synthesis of a high-affinity (nanomolar binding) opioid receptor peptidomimetic with selectivity for MOR in 1998.…”

The behavioral effects of a mixed efficacy antinociceptive peptide, VRP26, following chronic administration in mice

“…VRP26 (Dmt-c(SEtS)[DCys-Aci-DPen]-Ser(Glc)-NH 2 ) was synthesized as previously described (Mosberg et al 2014). …”

“…A standard curve for VRP26 was established using UV absorption at 230 nm. HPLC was performed on a Waters analytical HPLC; UV absorbance was monitored at 230 nm as described previously (Mosberg et al 2014) and used to determine the amount of drug delivered under test conditions.…”

“…We have previously described a cyclic pentapeptide, VRP26 (Figure 1), which displays low nanomolar affinity for both MOR and DOR, with selectivity relative to KOR as well as agonist activity at MOR similar to morphine and antagonism at DOR in vitro (Mosberg et al 2014). VRP26 produces dose-dependent antinociception in the warm water tail withdrawal (WWTW) assay in mice after peripheral administration and, more significantly, does not produce acute tolerance (Mosberg et al 2014).…”

“…VRP26 produces dose-dependent antinociception in the warm water tail withdrawal (WWTW) assay in mice after peripheral administration and, more significantly, does not produce acute tolerance (Mosberg et al 2014). VRP26 is therefore a good lead for further investigation of MOR agonist/DOR antagonist compounds as novel analgesics.…”