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. 2013 Mar 14;56(5):2139-49.
doi: 10.1021/jm400050y. Epub 2013 Feb 27.

Opioid peptidomimetics: leads for the design of bioavailable mixed efficacy μ opioid receptor (MOR) agonist/δ opioid receptor (DOR) antagonist ligands

Henry I Mosberg  1 , Larisa Yeomans, Aubrie A Harland, Aaron M Bender, Katarzyna Sobczyk-Kojiro, Jessica P Anand, Mary J Clark, Emily M Jutkiewicz, John R Traynor
Affiliations

Opioid peptidomimetics: leads for the design of bioavailable mixed efficacy μ opioid receptor (MOR) agonist/δ opioid receptor (DOR) antagonist ligands

Henry I Mosberg et al. J Med Chem. .

Abstract

We have previously described opioid peptidomimetic, 1, employing a tetrahydroquinoline scaffold and modeled on a series of cyclic tetrapeptide opioid agonists. We have recently described modifications to these peptides that confer a μ opioid receptor (MOR) agonist, δ opioid receptor (DOR) antagonist profile, which has been shown to reduce the development of tolerance to the analgesic actions of MOR agonists. Several such bifunctional ligands have been reported, but none has been demonstrated to cross the blood-brain barrier. Here we describe the transfer of structural features that evoked MOR agonist/DOR antagonist behavior in the cyclic peptides to the tetrahydroquinoline scaffold and show that the resulting peptidomimetics maintain the desired pharmacological profile. Further, the 4R diastereomer of 1 was fully efficacious and approximately equipotent to morphine in the mouse warm water tail withdrawal assay following intraperitoneal administration and thus a promising lead for the development of opioid analgesics with reduced tolerance.

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Figures

Figure 1
Figure 1
A. Structure of lead peptide 2 (JOM-13, Tyr-c(SS)[DCys-Phe-DPen]OH). B. Structure of lead peptidomimetic 1(4R). C. Superposition of proposed bioactive conformations of JOM-13 and 1(4R). (see ).
Figure 2
Figure 2
Antinociceptive activity of 1(4R) in mouse Warm Water Tail Withdrawal (WWTW) assay following intraperitoneal (ip) administration. Data represent response following pretreatment (−30 min) with saline (open circles) or naltrexone (NTX, filled circles) given by ip injection.
Figure 3
Figure 3
Time course of antinociception (WWTW assay) of 1(4R) (filled squares) and morphine (open circles) following ip administration.
Figure 4
Figure 4
Structures of Peptidomimetics.
Scheme 1
Scheme 1. Asymmetric Synthesis of Compound 7a
aReagents and conditions: (a) (Boc)2O, DMAP, DIEA, DCM, reflux; (b) (S)-2-methyl-CBS-oxazoborolidine, BH3·Me2S, THF; (c) phthalimide, DIAD, PPh3, THF; (d) N2H4·H2O, EtOH.
Scheme 2
Scheme 2. Preparation of Compounds 9a–da
aReagents and conditions: (a) benzene or naphthalene, P2O5, Al2O3, reflux; (b) 2-naphthalenyl boronic acid, PdCl2, K2CO3, acetone, H2O, 110°C, microwave irradiation; (c) 1-indanone, KOH, MeOH; (d) 10% Pd/C, H2, HCl, MeOH.
Scheme 3
Scheme 3. Preparation of Compounds 15a–da
aReagents and conditions: (a) 3-bromopropionyl chloride, K2CO3, DCM; (b) NaOtBu, DMF; (c) TfOH, DCE; (d) NH2OH·HCl, NaOAc, EtOH, H2O, reflux; (e) 10% Pd/C, H2, AcOH, MeOH; (f) Boc-Dmt, PyBOP, HOBt-Cl, DIEA, DMF; (g) TFA, DCM.
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