Enkephalin analogues with N-phenyl-N-(piperidin-2-ylmethyl)propionamide derivatives: Synthesis and biological evaluations

BIOORGANIC & MEDICINAL CHEMISTRY LETTERS

卷:26

Article

Deekonda, Srinivas¹  Cole, Jacob¹  Sunna, Sydney¹  Rankin, David²  Largent-Milnes, Tally M.²  Davis, Peg²  BassiriRad, Neemah M.²  Lai, Josephine²  Vanderah, Todd W.²  Porecca, Frank²  Hruby, Victor J.¹ 

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

[2] Univ Arizona, Dept Pharmacol, Tucson, AZ 85721 USA

关键词: Opioids;    Pain;    Opioid receptors;    Enkephalin;   

DOI  :  10.1016/j.bmcl.2015.10.081

来源: Elsevier

【 摘 要 】

N-Phenyl-N-(piperidin-2-ylmethyl)propionamide based bivalent ligands are unexplored for the design of opioid based ligands. Two series of hybrid molecules bearing N-phenyl-N-(piperidin-2-ylmethyl)propionamide derived small molecules conjugated with an enkephalin analogues with and without a linker (beta-alanine) were designed and synthesized. Both bivalent ligand series exhibited remarkable binding affinities from nanomolar to subnanomolar range at both mu and delta opioid receptors and displayed potent agonist activities as well. The replacement of Tyr with Dmt and introduction of a linker between the small molecule and enkephalin analogue resulted in highly potent ligands. Both series of ligands showed excellent binding affinities at both mu (0.6-0.9 nM) and delta (0.2-1.2 nM) opioid receptors respectively. Similarly, these bivalent ligands exhibited potent agonist activities in both MVD and GPI assays. Ligand 17 was evaluated for in vivo antinociceptive activity in non-injured rats following spinal administration. Ligand 17 was not significantly effective in alleviating acute pain. The most likely explanations for this low intrinsic efficacy in vivo despite high in vitro binding affinity, moderate in vitro activity are (i) low potency suggesting that higher doses are needed; (ii) differences in experimental design (i.e. non-neuronal, high receptor density for in vitro preparations versus CNS site of action in vitro); (iii) pharmacodynamics (i.e. engaging signalling pathways); (iv) pharmacokinetics (i.e. metabolic stability). In summary, our data suggest that further optimisation of this compound 17 is required to enhance intrinsic antinociceptive efficacy. (C) 2015 Elsevier Ltd. All rights reserved.

【 授权许可】

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