Development of novel enkephalin analogues that have enhanced opioid activities at both mu and delta opioid receptors

Abstract

Enkephalin analogues with a 4-anilidopiperidine scaffold have been designed and synthesized to achieve therapeutic benefit for the treatment of pain due to mixed mu and delta opioid agonist activities. Ligand 16, in which a Dmt-substituted enkephalin-like structure was linked to the N-phenyl-N-piperidin-4-yl propionamide moiety, showed very high binding affinities (0.4 nM) at mu and delta receptors with an increased hydrophobicity (aLogP = 2.96). This novel lead compound was found to have very potent agonist activities in MVD (1.8 nM) and GPI (8.5 nM) assays.

Figure 1

Chemical structure of opioid analogues

Figure 2

Design of opioid ligands.

Scheme 1^a

^a (a) stepwise coupling (BOP/HOBt/NMM, DMF, rt, 2-4 h) and deprotection (TFA, 0 °C, 20 min); (b) 1N KOH, EtOH; (c) NH₂-NH₂, DMF, 1 day; (d) succinic anhydride, EtOAc, 1 day; (e) BOP/HOBt/NMM, DMF, 4 h; (f) TFA, 0 °C, 20 min