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. 2015 Aug 19;6(8):1428-35.
doi: 10.1021/acschemneuro.5b00100. Epub 2015 May 13.

Asymmetric synthesis and in vitro and in vivo activity of tetrahydroquinolines featuring a diverse set of polar substitutions at the 6 position as mixed-efficacy μ opioid receptor/δ opioid receptor ligands

Aaron M Bender  1 , Nicholas W Griggs  2 , Jessica P Anand  2 , John R Traynor  2 , Emily M Jutkiewicz  2 , Henry I Mosberg  1   3
Affiliations

Asymmetric synthesis and in vitro and in vivo activity of tetrahydroquinolines featuring a diverse set of polar substitutions at the 6 position as mixed-efficacy μ opioid receptor/δ opioid receptor ligands

Aaron M Bender et al. ACS Chem Neurosci. .

Abstract

We previously reported a small series of mixed-efficacy μ opioid receptor (MOR) agonist/δ opioid receptor (DOR) antagonist peptidomimetics featuring a tetrahydroquinoline scaffold and showed the promise of this series as effective analgesics after intraperitoneal administration in mice. We report here an expanded structure-activity relationship study of the pendant region of these compounds and focus in particular on the incorporation of heteroatoms into this side chain. These analogues provide new insight into the binding requirements for this scaffold at MOR, DOR, and the κ opioid receptor (KOR), and several of them (10j, 10k, 10m, and 10n) significantly improve upon the overall MOR agonist/DOR antagonist profile of our previous compounds. In vivo data for 10j, 10k, 10m, and 10n are also reported and show the antinociceptive potency and duration of action of compounds 10j and 10m to be comparable to those of morphine.

Keywords: Opioid; dependence; intraperitoneal; mixed efficacy; tetrahydroquinoline; tolerance.

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Figures

Figure 1
Figure 1. Bifunctional MOR/DOR Ligandsa
a. Compound a from Ref. 17
Figure 2
Figure 2
Crystal structure of (R)-6-benzyl-1-(tert-butoxycarbonyl)-1,2,3,4-tetrahydroquinolin-4-aminium chloride
Figure 3
Figure 3. Docking of 10g in the MOR active site.a
a. Key hydrophobic contacts are highlighted in red (I144, V143, W133).
Figure 4
Figure 4. Overlay of 10k in the MOR, DOR and KOR active site.a
a. Grey residues = MOR, Yellow = DOR, Purple = KOR.
Figure 5
Figure 5. Dose response curve for compounds 10j,k,m,n.a
a Cumulative antinociceptive dose response curves in the mouse WWTW assay for 10j,k,m,n after intraperitoneal administration (n = 3-6) plotted as average ± SEM.
Figure 6
Figure 6. Time course for compounds 10j and 10m.a
a. Time course of antinociceptive response in the mouse WWTW assay after a cumulative dose of 10 mg/kg ip administration over time for 10j and 10m. Plotted as average ± SEM.
Scheme 1
Scheme 1. Synthesis of intermediates 4a-c, f-la
a Reagents and conditions: (a) 3-bromopropionyl chloride, K2CO3, DCM, r.t.; (b) NaOtBu, DMF, r.t.; (c) TfOH, DCE, r.t.; (d) (Boc)2O, DMAP, DIPEA, DCM, reflux; (e) NBS, benzoyl peroxide, CCl4, reflux; (f) boronic acid or pinacol ester, Pd(dppf)Cl2, K2CO3, acetone, water, 100°C w/microwave irradiation; (g) secondary amine, K2CO3, DMF, r.t.
Scheme 2
Scheme 2. Synthesis of intermediates 4d-e.a
a Reagents and conditions: (a) 3-bromopropionyl chloride, K2CO3, DCM, r.t.; (b) NaOtBu, DMF, r.t.; (c) TfOH, DCE, r.t.; (d) (Boc)2O, DMAP, DIPEA, DCM, reflux.
Scheme 3
Scheme 3. Final steps in synthesis of 10a-oa
a Reagents and conditions: (h) (R)-(+)-2-methyl-2-propanesulfinamide, Ti(OEt)4, THF, reflux; (i) NaBH4, THF; (j) conc. HCl, 1,4-dioxane, r.t.; (k) Boc-L-Dmt, PyBOP, DIPEA, HOBt-Cl, DMF, r.t.; (l) TFA, DCM, r.t.; (m) (Ac)2O, pyridine.
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References

    1. Benyamin R, Trescot AM, Datta S, Buenaventura R, Adlaka R, Sehgal N, Glaser SE, Vallejo R. Opioid Complications and Side Effects. Pain Physician. 2008;11:S105–120. - PubMed
    1. Ananthan S. Opioid Ligands With Mixed μ/δ Opioid Receptor Interactions: An Emerging Approach to Novel Analgesics. The AAPS Journal. 2006;8:119–125. - PMC - PubMed
    1. Schiller PW. Bi- or Multifunctional Opioid Peptide Drugs. Life Sci. 2010;86:598–603. - PMC - PubMed
    1. Hepburn MJ, Little PJ, Gingras J, Kuhn CM. Differential Effects of Naltrindole on Morphine-Induced Tolerance and Physical Dependence in Rats. J. Pharm. Exp. Ther. 1997;281:1350–1356. - PubMed
    1. Abdelhamid EE, Sultana M, Portoghese PS, Takemori AE. Selective Blockage of Delta Opioid Receptors Prevents the Development of Morphine Tolerance and Dependence in Mice. J. Pharm. Exp. Ther. 1991;258:299–303. - PubMed

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