Understanding the structural requirements of 4-anilidopiperidine analogues for biological activities at mu and delta opioid receptors

Abstract

New 4-anilidopiperidine analogues in which the phenethyl group of fentanyl was replaced by several aromatic ring-contained amino acids (or acids) were synthesized to study the biological effect of the substituents on mu and delta opioid receptor interactions. These analogues showed broad (47 nM-76 microM) but selective (up to 17-fold) binding affinities at the mu opioid receptor over the delta opioid receptor, as predicted from the message-address concept.

Figure 1

Opioid ligands.

Figure 2

(a) X-ray structure of 3. (b) The lowest energy conformer of 3. (c) Superimposition of 3 (black) and Dmt-Tic (blue). H-bond are represented by red dashed lines. For simplicity, nonpolar hydrogens are omitted in the structures.

Scheme 1

Synthesis of 4-anilidopiperidine analogues. Reagents and conditions: (a) 1.1 equiv BOP, 1.1 equiv HOBt, 2.2 equiv NMM, rt, 2–4 h, 85–95%; (b) TFA, 0 °C, 20 min, quantitative.