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. 2016 May 26;59(10):4985-98.
doi: 10.1021/acs.jmedchem.6b00308. Epub 2016 May 16.

Effects of N-Substitutions on the Tetrahydroquinoline (THQ) Core of Mixed-Efficacy μ-Opioid Receptor (MOR)/δ-Opioid Receptor (DOR) Ligands

Affiliations

Effects of N-Substitutions on the Tetrahydroquinoline (THQ) Core of Mixed-Efficacy μ-Opioid Receptor (MOR)/δ-Opioid Receptor (DOR) Ligands

Aubrie A Harland et al. J Med Chem. .

Abstract

N-Acetylation of the tetrahydroquinoline (THQ) core of a series of μ-opioid receptor (MOR) agonist/δ-opioid receptor (DOR) antagonist ligands increases DOR affinity, resulting in ligands with balanced MOR and DOR affinities. We report a series of N-substituted THQ analogues that incorporate various carbonyl-containing moieties to maintain DOR affinity and define the steric and electronic requirements of the binding pocket across the opioid receptors. 4h produced in vivo antinociception (ip) for 1 h at 10 mg/kg.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Peptidomimetic scaffold and N-substitutions; *previously published in ref (8), **previously published in ref (9).
Scheme 1
Scheme 1. Synthesis of N-Acylated Benzyl Pendant Analogues 4c4j
(a) neat acid anhydride (excess), 100 °C, 24 h (for compunds 2c, 2d); (b) acid chloride (eq), DCM, (for 2ej); (c) (R)-t-butanesulfinamide (2–3 equiv), THF, Ti(OEt)4 (4–6 equiv), 0 °C, then reflux at 75 °C; (d) NaBH4 (6 equiv), THF, −50 °C to RT, then MeOH, RT; (e) HCl (6 equiv), dioxane, RT; (f) diBoc-Dmt (1.05 equiv), PyBOP (1 equiv), 6Cl-HOBt (1 equiv), DIPEA (10 equiv), DMF, RT; (g) 1:1 TFA:DCM (excess). Note: not all crude final product was purified; as such a yield was not calculated.
Scheme 2
Scheme 2. Synthesis of N-Alkylated Benzyl Pendant Analogues 4k4m
(a) Boc2O (1.2–2 equiv), DMAP (0.1 equiv), DIPEA (1.2–2 equiv), DCM, 60 °C; (b) (R)-t-butanesulfinamide (2–3 equiv), THF, Ti(OEt)4 (4–6 equiv), 0 °C, then reflux at 75 °C; (c)NaBH4 (6 equiv), THF, −50 °C to RT, then MeOH, RT; (d) 1:1 TFA:DCM (excess); (e) HCl (6 equiv), dioxane, RT; (f) diBoc-Dmt (1.05 equiv), PyBOP (1 equiv), 6Cl-HOBt (1 equiv), DIPEA (10 equiv), DMF, RT; (g) Nal (2 equiv), 2-chloroacetamide (2 equiv), then DIPEA (1.5 equiv); (h) ethyl 2-bromoacetate (10 equiv), K2CO3 (2 equiv), CH3CN, 24 h; (i) LiOH (excess), EtOH, 60 °C, 2.5 h; (j) 3 N HCl (excess), RT. *Yield was higher, but the product was difficult to purify. Therefore, only 1.6 mg of 95% pure product was isolated, which was sufficient for opioid receptor binding and efficacy assays.
Scheme 3
Scheme 3. Synthesis of N-Acylated 2-Methylnaphthyl Pendant Analogues 15c15e
(f) 2-Naphthalenylboronic acid, Pd(dppf)Cl2, K2CO3, 3:1 acetone:H2O; (g) 1:1 TFA:DCM; (h) neat acid anhydride, reflux, 24 h (for 15c and 15d); (i) MeCOOCl, DCM, RT, 16 h (for 15e); (j) (R)-t-butanesulfinamide, THF, Ti(OEt)4, 0 °C, then reflux at 75 °C; (k) NaBH4, THF, – 50 °C to RT, 3 h, then MeOH, RT; (l) HCl, dioxane, RT, 3 h; (m) diBoc-Dmt, PyBOP, 6Cl-HOBt, DIPEA, DMF, RT. *Not all of the crude compound was purified, so yield was not calculated or appears low.
Figure 2
Figure 2
(A) Cumulative antinociceptive dose response curves of select benzyl pendant analogues (n = 3 for all analogues) in the mouse WWTW assay following ip administration. Plotted as average ± SEM. ****, p < 0.0001 for 4a and 4h for the 10 mg/kg dose when compared to baseline, p < 0.001 for 4f when compared to baseline (not indicated on graph). (B) Time course of antinociception of 4a and 4h (n = 3) in the mouse WWTW assay following ip administration of 10 mg/kg. Plotted as average ± SEM. Data for 4a from ref (8).
Figure 3
Figure 3
(A) Structure of 4g (teal) and 4j (magenta) bound in the active conformation of DOR with the area of the binding pocket occupied by the acyl chain circled (black). (B) Structure of 4k (green) bound in the active conformation of KOR with a potential polar contact between E297 and the terminal amide of the ligand which could be responsible for the increased KOR affinity and efficacy.

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