Effect of anchoring 4-anilidopiperidines to opioid peptides

Abstract

We report here the design, synthesis, and in vitro characterization of new opioid peptides featuring a 4-anilidopiperidine moiety. Despite the fact that the chemical structures of fentanyl surrogates have been found suboptimal per se for the opioid activity, the corresponding conjugates with opioid peptides displayed potent opioid activity. These studies shed an instructive light on the strategies and potential therapeutic values of anchoring the 4-anilidopiperidine scaffold to different classes of opioid peptides.

Scheme 1

Attachment of Fmoc and phthaloyl amino acids to 4-anilino-1-phenethyl-piperidine. Reagents and conditions: (i) Fmoc-AA-Cl (AA: Gly, Phe), DCM/10% NaHCO₃ in water, 0 °C (83% and 49%, respectively); (ii) Pht-Gly-Cl, TEA or DIPEA, DCM, 0 °C; (iii) N₂H₄·nH₂O, ethanol, reflux; (iv) see Ref. , R:Me (7), CF₃ (8), Et (9), Ph (10), –NHEt (11), –CH(Bzl)(NHCOCH₃) (12).

Scheme 2

Our strategies to introduce 4-anilidopiperidine functionality to opioid ligands. Reagents and conditions: (A) stepwise solution phase peptide synthesis, analogs 13–17; (B) reductive alkylation on solid support using (i) 4-(4-formyl-3-methoxy-phenoxy)butyryl AM (BAL) resin, NaBH(OAc)₃, DMF/DCM (1/3), (ii) Fmoc-AA-OH, HOBt, HBTU, DIPEA in DMF, (iii) 50% Piperidine in DMF, and (iv) TFA/i-PrSiH₃/H₂O (90/5/5); (C) N-side chain modification by method A: Merrifield resin (R³=O, R¹ = Boc, R² = Fmoc), (i) 50% Piperidine in DMF, (ii) p-nitrochloroformate, DIPEA, DCM, 1 h, (iii) 2–3 equiv of 3-aminofentanyl, microwave in a closed vessel for 1 h at 80 °C, (iv) 50% TFA in DCM, (v) SPPS followed by TFMSA cleavage; method B: 2-chlorotrityl resin (R³=O, R¹ = Fmoc, R² = Alloc), (i) Pd(PPh₃)₄, PhSiH₃ in DCM, (ii) p-nitrochloroformate, DIPEA, DCM, 1 h, (iii) 2–3 equiv of 3-aminofentanyl, microwave in a closed vessel for 1 h at 80 °C, (iv) 50% piperidine in DMF, (v) SPPS followed by TFA cleavage; method C: MBHA resin (R³ = Val-NH, R¹ = Fmoc, R² = Boc), (i) 50% TFA in DCM, (ii) p-nitrochloroformate, DIPEA, DCM, 1 h, (iii) 2–3 equiv of 3-aminofentanyl, microwave in a closed vessel for 1 h at 80 °C, (iv) 50% piperidine in DMF, (v) SPPS followed by TFMSA cleavage; (D) C-side chain modification using (i) Fmoc-Glu(Boc)-OH, HOBt, DIC, DMF→50% TFA in DCM→5% DIEA in DCM→amine (1, 5, 3-aminofentanyl), HOBt, DIC, microwave in DMF for 5 min at 80 °C→25% piperidine in DMF, (ii) solid phase peptide synthesis, and (iii) TFMSA cleavage.