Discovery, synthesis, and molecular pharmacology of selective positive allosteric modulators of the δ-opioid receptor

J Med Chem. 2015 May 28;58(10):4220-9. doi: 10.1021/acs.jmedchem.5b00007. Epub 2015 May 7.


Allosteric modulators of G protein-coupled receptors (GPCRs) have a number of potential advantages compared to agonists or antagonists that bind to the orthosteric site of the receptor. These include the potential for receptor selectivity, maintenance of the temporal and spatial fidelity of signaling in vivo, the ceiling effect of the allosteric cooperativity which may prevent overdose issues, and engendering bias by differentially modulating distinct signaling pathways. Here we describe the discovery, synthesis, and molecular pharmacology of δ-opioid receptor-selective positive allosteric modulators (δ PAMs). These δ PAMs increase the affinity and/or efficacy of the orthosteric agonists leu-enkephalin, SNC80 and TAN67, as measured by receptor binding, G protein activation, β-arrestin recruitment, adenylyl cyclase inhibition, and extracellular signal-regulated kinases (ERK) activation. As such, these compounds are useful pharmacological tools to probe the molecular pharmacology of the δ receptor and to explore the therapeutic potential of δ PAMs in diseases such as chronic pain and depression.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Arrestins / metabolism
  • Benzamides / pharmacology
  • Binding, Competitive
  • CHO Cells
  • Cell Membrane / drug effects
  • Cell Membrane / metabolism
  • Chemistry Techniques, Synthetic
  • Cricetulus
  • Drug Discovery
  • Drug Evaluation, Preclinical / methods
  • Enkephalin, Leucine / pharmacology
  • Enzyme Activation / drug effects
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Molecular Structure
  • Molecular Targeted Therapy
  • Piperazines / pharmacology
  • Protein Binding
  • Quinolines / pharmacology
  • Receptors, Opioid, delta / metabolism*
  • Structure-Activity Relationship*
  • beta-Arrestins


  • Arrestins
  • Benzamides
  • Piperazines
  • Quinolines
  • Receptors, Opioid, delta
  • TAN 67
  • beta-Arrestins
  • 4-(alpha-(4-allyl-2,5-dimethyl-1-piperazinyl)-3-methoxybenzyl)-N,N-diethylbenzamide
  • Enkephalin, Leucine
  • Extracellular Signal-Regulated MAP Kinases