PMC

Modifications to THQ Scaffold

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 .

(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.

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.

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

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 .

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

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.

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)