Design and synthesis of novel bivalent ligands (MOR and DOR) by conjugation of enkephalin analogues with 4-anilidopiperidine derivatives

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:25

Article

Deekonda, Srinivas¹  Wugalter, Lauren¹  Rankin, David²  Largent-Milnes, Tally M.²  Davis, Peg²  Wang, Yue²  Bassirirad, Neemah M.²  Lai, Josephine²  Kulkarni, Vinod¹  Vanderah, Todd W.²  Porreca, Frank²  Hruby, Victor J.¹ 

[1] Univ Arizona, Dept Chem & Biochem, Tucson, AZ 85721 USA

[2] Univ Arizona, Dept Pharmacol, Tucson, AZ 85724 USA

关键词: Opioids;    Opioid receptors;    Bivalent ligands;    Enkephalins;   

DOI  :  10.1016/j.bmcl.2015.07.064

来源: Elsevier

【 摘 要 】

We describe the design and synthesis of novel bivalent ligands based on the conjugation of 4-anilidopiperidine derivatives with enkephalin analogues. The design of non-peptide analogues is explored with 5-amino substituted (tetrahydronaphthalen-2yl) methyl containing 4-anilidopiperidine derivatives, while non-peptide-peptide ligands are explored by conjugating the C-terminus of enkephalin analogues (H-Xxx-DAla-Gly-Phe-OH) to the amino group of 4-anilidopiperidine small molecule derivatives with and without a linker. These novel bivalent ligands are evaluated for biological activities at mu and delta opioid receptors. They exhibit very good affinities at mu and delta opioid receptors, and potent agonist activities in MVD and GPI assays. Among these the lead bivalent ligand 17 showed excellent binding affinities (0.1 nM and 0.5 nM) at mu and delta opioid receptors respectively, and was found to have very potent agonist activities in MVD (56 +/- 5.9 nM) and GPI (4.6 +/- 1.9 nM) assays. In vivo the lead bivalent ligand 17 exhibited a short duration of action (< 15 min) comparable to 4-anilidopiperidine derivatives, and moderate analgesic activity. The ligand 17 has limited application against acute pain but may have utility in settings where a highly reversible analgesic is required. (C) 2015 Elsevier Ltd. All rights reserved.

【 授权许可】

Free