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. 2015 Nov 25;58(22):8952-69.
doi: 10.1021/acs.jmedchem.5b01270. Epub 2015 Nov 13.

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

Aubrie A Harland  1 , Larisa Yeomans  1 , Nicholas W Griggs  1 , Jessica P Anand  1 , Irina D Pogozheva  1 , Emily M Jutkiewicz  1 , John R Traynor  1 , Henry I Mosberg  1
Affiliations

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

Aubrie A Harland et al. J Med Chem. .

Abstract

In a previously described peptidomimetic series, we reported the development of bifunctional μ-opioid receptor (MOR) agonist and δ-opioid receptor (DOR) antagonist ligands with a lead compound that produced antinociception for 1 h after intraperitoneal administration in mice. In this paper, we expand on our original series by presenting two modifications, both of which were designed with the following objectives: (1) probing bioavailability and improving metabolic stability, (2) balancing affinities between MOR and DOR while reducing affinity and efficacy at the κ-opioid receptor (KOR), and (3) improving in vivo efficacy. Here, we establish that, through N-acetylation of our original peptidomimetic series, we are able to improve DOR affinity and increase selectivity relative to KOR while maintaining the desired MOR agonist/DOR antagonist profile. From initial in vivo studies, one compound (14a) was found to produce dose-dependent antinociception after peripheral administration with an improved duration of action of longer than 3 h.

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Figures

Figure 1
Figure 1
Modifications to THQ Scaffold
Figure 2
Figure 2
Cumulative antinociceptive dose response curves of select analogues (n=3 for all analogues, except for 14a n=6) in the mouse WWTW assay following ip administration. Plotted as average +/− S.E.M. ****, p < 0.0001 for 14a, 14f, 14i, 14j for the 10 mg/kg dose when compared to baseline. Data for 14i from ref .
Figure 3
Figure 3
Time course of antinociception of 14a and 14i (n=6) in the mouse WWTW assay following ip administration of 10 mg/kg. Plotted as average +/− S.E.M. Data for 14i from ref .
Figure 5
Figure 5
(A) 14j (purple) in DORinactive (DORi) with key residues shown. (B) 14a (teal) in DORi with key residues shown. Dashed lines represent calculated distances between ligand and receptor residues, indicating a possible interaction between N-acetyl moiety and Tyr129 that may increase binding affinity at DORi. (C) overlay of 14j (purple) and DIPP-NH2 (orange) in DORi. (D) Overlay of 14a (teal) and DIPP-NH2 (orange) in DORi.
Figure 6
Figure 6
Summary of in vivo activity following ip administration, cLogP, and molecular weight (MW, g/mol) for select compounds. Compounds 14e, 14o, 14p, 14l, 14m do not display antinociception following ip administration and structures are not shown. 1see ref. for in vivo activity.
Scheme 1
Scheme 1
Synthesis of THQ-Containing Analogues Diversified via Suzuki Coupling (a) 3-bromopropionyl chloride (1.02 eq), K2CO3 (2.05 eq), DCM, RT, (b) NaOtBu (1.05 eq), DMF, RT (c) TfOH (3 eq), DCE, RT (d) neat Ac2O (excees), refulx, (e) For synthesis of 6a and 6d: R2Bpin (2 eq), Pd(dppf)Cl2(0.1 eq), K2CO3 (3 eq), 3:1 acetone:H2O, MW 100°C, 300 W, (f) For synthesis of 6c and 6d: R2-B(OH)2 (2 eq), Ag2O (2.5 eq), Pd(dppf)Cl2 (0.1 eq), K2CO3 (3 eq), THF, MW 100°C, 300 W (g) Bco2O (1.2-2 eq), DMAP (0.1 eq), DIPEA (1.2-2 eq), DCM, 60°C
Scheme 2
Scheme 2
Synthesis of THQ-Containing Analogues via Condensation Reactions (a) 3-bromopropionyl chloride (1.02 eq), K2CO3 (2.05 eq), DCM, RT (b) NaOtBu (1.05 eq), DMF, RT (c) TfOH (3 eq), DCE, RT (d) For synthesis of 6e, 6g, 6g neat Ac2O (excess), reflux (e) For synthesis of 6h: Boc2O (1.2–2 eq), DMAP (0.1 eq), DIPEA (1.2–2 eq), DCM, 60°C
Scheme 3
Scheme 3
Completion of Synthesis of THQ-Containing Analogues (a) Dihydroquinolinone intermediate, 6a-h (1 eq), (R)-t-Butanesulfinamide (2–3 eq), THF, Ti(OEt)4 (4–6 eq), 0°C, then reflux at 75°C (b) NaBH4 (6 eq), THF, −50°C to RT, then MeOH, RT (c) HCl (6 eq), dioxane, RT (d) diBoc-DMT (1.05 eq), PyBOP (1 eq), 6Cl-HOBt (1 eq), DIPEA (10 eq), DMF, RT (e) 1:1 TFA:DCM (excess). Compounds 14i-14l previously published, see ref. . * indicates starting material was recovered, but not included in yield calculation.
Scheme 4
Scheme 4
Synthesis of THN-Containing Analogues (a) 15 (1 eq), (R)-t-Butanesulfinamide (2-3 eq), THF, Ti(OEt)4 (4-6 eq) 0°C, then refulx at 75°C (b) NaBH4 (4-6 eq), THF, −50°C to RT, then MeOH, RT (c) for synthesis of 18m, 18o, 18p: R2-Bpin (1 eq), pd(dppf)Cl2 (0.1 eq), K2CO3 (3 eq), 3:1 acetone:H2O,MW 110°C, 300 W (d) For synthesis of 18n: R2-B(OH)2 (2 eq), Ag2O (2.5 eq), pd(dppf)Cl2(0.1 eq), K2CO3 (3 eq), THF, MW 80°C, 300 W (e) HCl (6 eq), dioxane, RT(f) diBoc-DMT (1.05 eq), PyBOP (1 eq), 6Cl-HOBt (1 eq), DIPEA (10 eq), DMF, RT (g) 1:1 TFA:DCM (excess)
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