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. 2014 Apr 10;57(7):3148-53.
doi: 10.1021/jm5002088. Epub 2014 Mar 26.

Development of a bioavailable μ opioid receptor (MOPr) agonist, δ opioid receptor (DOPr) antagonist peptide that evokes antinociception without development of acute tolerance

Henry I Mosberg  1 , Larisa Yeomans, Jessica P Anand, Vanessa Porter, Katarzyna Sobczyk-Kojiro, John R Traynor, Emily M Jutkiewicz
Affiliations

Development of a bioavailable μ opioid receptor (MOPr) agonist, δ opioid receptor (DOPr) antagonist peptide that evokes antinociception without development of acute tolerance

Henry I Mosberg et al. J Med Chem. .

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.

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Figures

Figure 1
Figure 1
Structure of lead MOPr (ag)/DOPr (ant) peptide 1 (KSK103).
Figure 2
Figure 2
Antinociception as a function of dose observed for 4 in mouse warm water tail withdrawal assay following ip administration.
Figure 3
Figure 3
Antinociception (mouse WWTW assay) time course following 32 mg/kg ip dose of 4.
Figure 4
Figure 4
Latency to tail withdrawal observed for 4 (10 mg/kg, ip) with (right) and without (left) pretreatment with the opioid antagonist naltrexone.
Figure 5
Figure 5
Determination of acute tolerance to antinociceptive effect (mouse WWTW assay) of 4. Mice were treated with 10 mg/kg 4 (closed squares) or saline (open circles), and the time course of the antinociceptive response was determined. At t = 90 min (indicated by dashed vertical line) both groups of mice were injected with 10 mg/kg 4 and antinociceptive response was again examined.
Figure 6
Figure 6
Determination of acute tolerance to antinociceptive effect (mouse WWTW assay) of fentanyl. Mice were treated with 0.3 mg/kg fentanyl (closed squares) or saline (open circles), and the time course of the antinociceptive response was determined. At t = 120 min (indicated by dashed vertical line) both groups of mice were injected with 0.3 mg/kg fentanyl, and antinociceptive response was again examined.
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