Human native kappa opioid receptor functions not predicted by recombinant receptors: Implications for drug design

Sci Rep. 2016 Aug 5;6:30797. doi: 10.1038/srep30797.


If activation of recombinant G protein-coupled receptors in host cells (by drugs or other ligands) has predictive value, similar data must be obtained with native receptors naturally expressed in tissues. Using mouse and human recombinant κ opioid receptors transfected into a host cell, two selectively-acting compounds (ICI204448, asimadoline) equi-effectively activated both receptors, assessed by measuring two different cell signalling pathways which were equally affected without evidence of bias. In mouse intestine, naturally expressing κ receptors within its nervous system, both compounds also equi-effectively activated the receptor, inhibiting nerve-mediated muscle contraction. However, whereas ICI204448 acted similarly in human intestine, where κ receptors are again expressed within its nervous system, asimadoline was inhibitory only at very high concentrations; instead, low concentrations of asimadoline reduced the activity of ICI204448. This demonstration of species-dependence in activation of native, not recombinant κ receptors may be explained by different mouse/human receptor structures affecting receptor expression and/or interactions with intracellular signalling pathways in native environments, to reveal differences in intrinsic efficacy between receptor agonists. These results have profound implications in drug design for κ and perhaps other receptors, in terms of recombinant-to-native receptor translation, species-dependency and possibly, a need to use human, therapeutically-relevant, not surrogate tissues.

MeSH terms

  • Acetamides / pharmacology
  • Animals
  • Drug Design
  • HEK293 Cells
  • Humans
  • Intestinal Mucosa / metabolism*
  • Mice
  • Pyrrolidines / pharmacology
  • Receptors, Opioid, kappa / metabolism*
  • Recombinant Proteins / metabolism*
  • Signal Transduction
  • Species Specificity


  • Acetamides
  • Pyrrolidines
  • Receptors, Opioid, kappa
  • Recombinant Proteins
  • asimadoline